Conditions: HER2-positive Breast Cancer HER2-positive Gastric Cancer HER2-positive Colorectal Cancer HER2-expressing Non-small Cell Lung Cancer
Keywords: SBT6050 HER2 breast cancer gastric cancer colorectal cancer non-small cell lung cancer TLR8 trastuzumab deruxtecan tucatinib trastuzumab capecitabine
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
This study is designed to assess the safety and preliminary activity of SBT6050 in combination with trastuzumab deruxtecan (Part 1) or tucatinib plus trastuzumab +/- capecitabine (Part 2). Participants will be enrolled into each Arm based on cancer diagnosis and prior therapies.

Detailed description:

Arms:
arm 1: SBT6050 plus trastuzumab deruxtecan arm 2: SBT6050 plus trastuzumab deruxtecan arm 3: SBT6050 plus tucatinib, trastuzumab, and capecitabine arm 4: SBT6050 plus tucatinib and trastuzumab

Interventions: intervention 1: SBT6050 intervention 2: trastuzumab deruxtecan intervention 3: tucatinib intervention 4: trastuzumab intervention 5: capecitabine intervention 6: trastuzumab deruxtecan
Intervention descriptions: intervention 1: Dose range of 0.45 to 0.6 mg/kg by subcutaneous (SC) injection in 21-day cycles intervention 2: 5.4 mg/kg by intravenous (IV) infusion in 21-day cycles intervention 3: 300 mg by mouth (PO) twice daily (BID) intervention 4: 8 mg/kg loading dose (first dose), then 6 mg/kg maintenance dose (subsequent doses) IV infusion in 21-day cycles intervention 5: 1000 mg/m2 PO BID for 14 days of each 21-day cycle intervention 6: 6.4 mg/kg by IV infusion in 21-day cycles

Protocol document:
Prot_SAP_000.pdf: 
COVER PAGE 
Official Study Title: 
An Open-label, Phase 1/2, Dose-escalation and 
Expansion Study of SBT6050 Combined With 
Other HER2-directed Therapies in Subjects With 
Pretreated Unresectable Locally Advanced and/or 
Metastatic HER2-expressing or HER2-amplified 
Cancers 
NCT Number: 
NCT05091528 
Document Date: 
12 April 2022 
 




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2 
TABLE OF CONTENTS 
1 
TITLE PAGE .................................................................................................................................................. 1 
2 
TABLE OF CONTENTS ................................................................................................................................ 2 
3 
SUMMARY .................................................................................................................................................... 3 
4 
STUDY PLAN ................................................................................................................................................ 4 
4.1 
Overall Design....................................................................................................................................... 4 
4.2 
End of Treatment ................................................................................................................................... 4 
4.3 
Follow-up and End of Study ................................................................................................................. 5 
4.4 
Collection of Study Assessments .......................................................................................................... 5 
4.4.1 
Safety Measurements ................................................................................................................ 5 
4.4.2 
Efficacy Measurements ............................................................................................................ 5 
4.4.3 
Other Measurements ................................................................................................................. 6 
5 
SCHEDULE OF ASSESSMENTS FOR PART 1: SBT6050 COMBINED WITH TRASTUZUMAB 
DERUXTECAN .............................................................................................................................................. 7 
6 
SCHEDULE OF ASSESSMENTS FOR PART 2: SBT6050 COMBINED WITH TUCATINIB PLUS 
TRASTUZUMAB WITH OR WITHOUT CAPECITABINE ........................................................................ 9 
 


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Summary of Changes for Protocol Addendum 1 
Change 
Rationale 
End of treatment for subjects enrolled in the 
study or actively receiving study drug at the time 
of Sponsor’s decision to prematurely terminate 
the study. Subjects who experience toxicity 
considered related to any component of study 
treatment should discontinue study treatment. 
Subjects who experience toxicity related to any study drug 
should discontinue all study treatment. 
Minimize study-related assessments for safety 
and efficacy for the duration of study treatment 
for subjects enrolled in the study or actively 
receiving study drug at the time of the Sponsor’s 
decision to prematurely terminate the study. 
Remove requirement for collection of further 
research samples for subjects on treatment. 
To minimize the extent of data collection following the 
Sponsor decision to terminate the SBT6050-201 study and 
reduce subject burden. 
Study-related assessments in follow-up limited 
to safety and disease status per institutional 
standard of care. 
To minimize the extent of data collection following the 
Sponsor decision to terminate the SBT6050-201 study and 
continue to ensure subject safety while on treatment. 


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3 
SUMMARY 
This is an addendum to the SBT6050-201 Protocol A01. This addendum provides further 
guidance to the Investigators regarding protocol modifications coming from the Sponsor decision 
to terminate the clinical trial.  
This addendum describes changes to: 
1. End of treatment for subjects enrolled in the study or actively receiving study drug at the 
time of Sponsor decision to prematurely terminate the clinical trial 
2. Protocol-defined assessments in follow-up for treated subjects 
3. Protocol-defined study assessments for safety and efficacy for subjects enrolled in the 
study actively receiving study drug 
Refer to SBT6050-201 Protocol A01 for details regarding the original study design and schedule 
of assessments. A detailed summary of the nonclinical and clinical SBT6050 safety data is 
provided in the Investigator Brochure. 
4 
STUDY PLAN 
4.1 Overall Design 
This is a phase 1/2 open-label, multicenter, dose-escalation and expansion study designed to 
evaluate the safety, tolerability, PK, pharmacodynamics, immunogenicity, and efficacy of 
SBT6050 in combination with trastuzumab deruxtecan (T-DXd; Part 1) or tucatinib and 
trastuzumab ± capecitabine (Part 2). 
On 31 March 2022, the Sponsor decided to prematurely terminate the study and subject 
enrollment was terminated. 
4.2 End of Treatment 
Subjects enrolled in the screening period and those receiving active treatment at the time of 
the Sponsor decision may continue to receive treatment with SBT6050 in combination with 
T-DXd (Part 1) or tucatinib and trastuzumab ± capecitabine (Part 2) until any of the 
following reasons (whichever occurs first): 
• completed 2 years of treatment with SBT6050 
• progression of disease 
• development of unacceptable toxicity 
• confirmed pregnancy 
• death 
• withdrawal of consent 
• subject decision 


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• lost to follow-up 
• other reason (eg, Investigator decision) 
Subjects who discontinue one of the study drugs due to toxicity considered related to that 
drug should discontinue all study treatment. 
4.3 Follow-up and End of Study 
Subject follow-up will continue after discontinuation of treatment through the required 30-
day safety follow-up period until death, withdrawal of consent, lost to follow-up, or other 
reason. 
End of study is defined as the time the last subject has completed the safety follow-up period 
after the last dose of study treatment (30 days), has died, is lost to follow-up, or has 
withdrawn consent. 
4.4 Collection of Study Assessments 
Subjects who have not received at least 2 cycles of study treatment at the time of the Sponsor 
decision will continue to have safety and response assessments captured as defined in 
Section 5 and Section 6 through completion of Cycle 2, including a tumor re-assessment at 
Week 6. Samples for research purposes will no longer be collected. 
After Cycle 2, all subjects will have study assessments collected as outlined in the sections 
below. 
4.4.1 Safety Measurements 
Subjects who completed Cycle 2 and are continuing on study treatment will continue to be 
assessed for safety during treatment and follow-up per the institutional standard of care and 
the currently approved labeling for trastuzumab deruxtecan (Part 1) or the tucatinib 
combination (Part 2) and considering the safety profile of SBT6050 described in the 
Investigator Brochure. 
The Sponsor will continue to collect data for serious adverse events (SAEs) for all subjects 
until the subject discontinues treatment through the required 30-day safety follow-up period 
unless the subject withdraws consent. 
SAEs should be reported according to Section 6.9 of the protocol. 
4.4.2 Efficacy Measurements 
Disease progression will be evaluated per the institutional standard of care for all subjects. 
Disease status (progressed or not progressed) should be reported to the Sponsor following 
each tumor response assessment or every 3 months, whichever is sooner, and at 
discontinuation of treatment, unless the subject withdraws consent. 
Subject status should also be reported to the Sponsor at each SBT6050 dosing visit and at 
discontinuation of treatment unless the subject withdraws consent. 


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4.4.3 Other Measurements 
For all subjects, after Cycle 2 no further collection of study-related procedures or research 
samples per Section 6 of the protocol should be made. 
 


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5 
SCHEDULE OF ASSESSMENTS FOR PART 1: SBT6050 COMBINED WITH TRASTUZUMAB DERUXTECAN 
Procedure 
Screening/ 
Baseline 
Each Treatment Cycle is 21 Days 
Follow-upa 
Cycle 1 
Cycle 2 
Cycle 3+ 
 
D-28 to D1 
Day 1 
Day 2 
Day 4  
or Day 5 
Day 8 
Day 1 
Day 8 
Day 1 
30 days post 
last dose 
 
Visit window 
 
(24 ± 2 hrs) 
(72–96 hrs 
±2 hrs) 
(±1 day) 
(±2 day) 
(±1 day) 
(±2 day) 
(±7 days) 
 
 
Pre 
Post 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Confirmation of HER2 statusb 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
Xc 
 
 
 
 
X 
 
 
 
Medical history and current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
Pregnancy testd 
X 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B and C screening 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Hematology panele 
X 
Xc 
 
 
X 
X 
Predose 
X 
 
 
Chemistry panelf 
X 
Xc 
 
 
X 
X 
Predose 
X 
 
 
Thyroid panelg 
X 
 
 
 
 
 
 
 
 
 
Coagulation panelh 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
 
 
 
 
ECHO/MUGA 
X 
Per institutional standard of care while on treatment 
EGOG Performance Status 
X 
Xc 
 
 
 
 
X 
 
 
 
SpO2 
X 
X 
 
 
 
 
X 
 
 
 
Vital signs 
X 
Xi 
X 
X 
X 
Xi 
X 
 
 
MRI of brainj 
X 
 
 
 
 
 
 
 
 
 
Administer SBT6050k 
 
X 
 
 
 
X 
 
X 
 
Administer T-DXdk 
 
X 
 
 
 
X 
 
X 
 
AE/concomitant medication review 
X 
Collect from consent through Cycle 2, then per institutional standard of care while on treatment 
 
SAE review 
X 
Collect from consent to 30 days post last dose 
Tumor assessmentl 
X 
 
 
 
 
 
Week 6 then per institutional standard of 
care while on treatment 
 
Survival status 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; CRC = colorectal cancer; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = 
Eastern Cooperative Oncology Group; GEA = gastroesophageal adenocarcinoma; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 
receptor 2; HR = hour; IV = intravenously; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NSCLC = non-small-cell lung cancer; SAE = 
serious adverse event; SPO2 = oxygen saturation; SC = subcutaneously; T-DXd = trastuzumab deruxtecan. 
aSubjects will be followed 30 days after the last dose for survival, disease status, and SAEs until death, withdrawal of consent, lost to follow-up, or other reason. 
bThe most recent result to confirm HER2 status should be used. If documentation of a previous HER2 result is not available, archived tissue, slides, fresh tissue or 
blood sample must be submitted to either a local laboratory or a Sponsor-designated central laboratory to confirm HER2 expression or amplification. 


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Confirmatory HER2 testing may be obtained greater than 28 days prior to Cycle 1 Day 1, if separate consent for confirmatory HER2 pre-testing is signed (see 
Section 6.1 of the protocol). 
cAssessments do not need to be repeated if performed within 72 hours of first dose of SBT6050. 
dFor subjects of childbearing potential; to be performed within 14 days of Cycle 1 Day 1. 
eHematology panel consists of erythrocytes, hemoglobin, hematocrit, platelets, leucocytes and differential count (neutrophils, eosinophils, basophils, monocytes, 
and lymphocytes, as percentages and absolute values, if available); analyses for complete blood count, white blood cell differential, and reticulocyte count will 
also be performed. 
fChemistry panel consists of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, calcium, phosphate, magnesium, creatinine, total protein, albumin, 
glucose, total and direct bilirubin, amylase, alkaline phosphatase (ALP), ALT, AST, lactate dehydrogenase, γ glutamyl transferase, lipase, triglycerides, and 
troponin. Creatinine clearance, only required for eligibility criteria at Screening/Baseline, will be calculated using the Cockcroft-Gault formula. 
gThyroid panel consists of triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). 
hCoagulation panel consists of PT/international normalized ratio (INR) and PTT (or, depending on institutional standard, aPTT). 
iVital signs will be taken predose SBT6050 and postdose 15, 30, 45, 60 minutes (+/-15 minutes) SBT6050 and then immediately following the end of the T-DXD 
infusion (+15 minutes) on dosing days. 
jRequired for all subjects with breast cancer or NSCLC and for subjects with gastric or GEJ cancer or CRC who have a history of CNS metastases or have signs 
or symptoms suggestive of CNS metastasis. 
kSee Protocol Section 5.1 for a description of treatments to be administered during the study. SBT6050 should be administered first, followed by T-DXd. T-DXd 
infusion should begin at least 15 minutes after the injection of SBT6050. 
lTumor assessment by CT, PET/CT (if diagnostic-quality CT scan included), or MRI. 
 


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6 
SCHEDULE OF ASSESSMENTS FOR PART 2: SBT6050 COMBINED WITH TUCATINIB PLUS TRASTUZUMAB 
WITH OR WITHOUT CAPECITABINE 
Procedure 
Screening/ 
Baseline 
Each Treatment Cycle is 21 Days 
FUa 
Cycle 1 
Cycle 2 
Cycle 3+ 
 
D-28 to D1 
Day 1 
Day 2 
Day 4  
or Day 5 
Day 8 
Day 1 
Day 8 
Day 1 
30 days post 
last dose 
 
Visit window 
 
(24 ± 2 hrs) 
(72–96 hrs 
±2 hrs) 
(±1 day) 
(±2 day) 
(±1 day) 
(±2 day) 
(±7 days) 
 
 
Pre 
Post 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Confirmation of HER2 statusb 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
Xc 
 
 
 
 
X 
 
 
 
Medical history and current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
Pregnancy testd 
X 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B and C screening 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Hematology panele 
X 
Xc 
 
 
X 
X 
Predose 
X 
 
 
Chemistry panelf 
X 
Xc 
 
 
X 
X 
Predose 
X 
 
 
Thyroid panelg 
X 
 
 
 
 
 
 
 
 
 
Coagulation panelh 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
 
 
 
 
ECHO/MUGA 
X 
Per institutional standard of care while on treatment 
EGOG Performance Status 
X 
Xc 
 
 
 
 
X 
 
 
 
SpO2 
X 
X 
 
 
 
 
X 
 
 
 
Vital signs 
X 
Xi 
X 
X 
X 
Xi 
X 
 
 
MRI of brainj 
X 
 
 
 
 
 
 
 
 
 
Administer SBT6050k 
 
X 
 
 
 
X 
 
X 
 
Administer trastuzumabk 
 
X 
 
 
 
X 
 
X 
 
Administer tucatinibk 
 
PO BID throughout the duration of the study 
 
Administer capecitabine, if 
applicablek 
 
PO BID on Days 1–14 of every 21-day cycle 
X 
 
AE/concomitant medication review 
X 
Collect from consent through Cycle 2, then per institutional standard of care while on treatment 
 
SAE review 
X 
Collect from consent to 30 days post last dose 
Tumor assessmentl 
X 
 
 
 
 
 
Week 6 then per institutional standard of 
care while on treatment 
 
Survival status 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; CRC = colorectal cancer; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = 
Eastern Cooperative Oncology Group; GEA = gastroesophageal adenocarcinoma; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 
receptor 2; HR = hour; IV = intravenously; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NSCLC = non-small-cell lung cancer; SAE = 
serious adverse event; SPO2 = oxygen saturation; SC = subcutaneously. 


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aSubjects will be followed 30 days after the last dose for survival, disease status, and SAEs until death, withdrawal of consent, lost to follow-up, or other reason. 
bThe most recent result to confirm HER2 status should be used. If documentation of a previous HER2 result is not available, archived tissue, slides, fresh tissue or 
blood sample must be submitted to either a local laboratory or a Sponsor-designated central laboratory to confirm HER2 expression or amplification. 
Confirmatory HER2 testing may be obtained greater than 28 days prior to Cycle 1 Day 1, if separate consent for confirmatory HER2 pre-testing is signed (see 
Section 6.1 of the protocol). 
cAssessments do not need to be repeated if performed within 72 hours of first dose of SBT6050. 
dFor subjects of childbearing potential; to be performed within 14 days of Cycle 1 Day 1. 
eHematology panel consists of erythrocytes, hemoglobin, hematocrit, platelets, leucocytes and differential count (neutrophils, eosinophils, basophils, monocytes, 
and lymphocytes, as percentages and absolute values, if available); analyses for complete blood count, white blood cell differential, and reticulocyte count will 
also be performed. 
fChemistry panel consists of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, calcium, phosphate, magnesium, creatinine, total protein, albumin, 
glucose, total and direct bilirubin, amylase, alkaline phosphatase (ALP), ALT, AST, lactate dehydrogenase, γ glutamyl transferase, lipase, triglycerides, and 
troponin. Creatinine clearance, only required for eligibility criteria at Screening/Baseline, will be calculated using the Cockcroft-Gault formula. 
gThyroid panel consists of triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). 
hCoagulation panel consists of PT/international normalized ratio (INR) and PTT (or, depending on institutional standard, aPTT). 
iVital signs will be taken predose SBT6050 and postdose 15, 30, 45, 60 minutes (+/-15 minutes) SBT6050 and then immediately following the end of the T-DXD 
infusion (+15 minutes) on dosing days. 
jRequired for all subjects with breast cancer or NSCLC and for subjects with gastric or GEJ cancer or CRC who have a history of CNS metastases or have signs 
or symptoms suggestive of CNS metastasis. 
kSee Protocol Section 5.1 for a description of treatments to be administered during the study. SBT6050 should be administered first, followed by trastuzumab. 
Trastuzumab infusion should begin at least 15 minutes after the injection of SBT6050. At Cycle 1/Day 1, tucatinib and capecitabine (if applicable) should also be 
taken after SBT6050 and trastuzumab in the clinic. On Day 1 of each cycle, study staff should review tucatinib and capecitabine (if applicable) compliance from 
previous cycle. 
lTumor assessment by CT, PET/CT (if diagnostic-quality CT scan included), or MRI. 
 




 
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PROTOCOL SYNOPSIS 
Protocol Number 
SBT6050-201 
Product Name 
SBT6050 
Version 
Amendment 1; 10-Jan-2022 
Sponsor 
Silverback Therapeutics, Inc. 
500 Fairview Avenue North, Suite 600 
Seattle, WA 98109 
Phase 
1/2 
Protocol Title 
An Open-label, Phase 1/2, Dose-escalation and Expansion Study of SBT6050 Combined With Other HER2-
directed Therapies in Subjects With Pretreated Unresectable Locally Advanced and/or Metastatic HER2-
expressing or HER2-amplified Cancers 
Study Objectives 
Part 1: Phase 1 Dose Escalation Cohorts: 
Primary 
• 
To estimate the maximum tolerated dose (MTD), if reached, and determine the recommended phase 2 
dose (RP2D) of SBT6050 when combined with trastuzumab deruxtecan (T-DXd) 
• 
To evaluate the safety and tolerability of SBT6050 and T-DXd 
Secondary 
• 
To assess preliminary efficacy of SBT6050 and T-DXd 
 
 
 
 
 
 
 
 
 
Part 1: Phase 2 Dose Expansion Cohorts: 
Primary 
• 
To assess efficacy of SBT6050 and T-DXd 
Secondary 
• 
To evaluate the safety and tolerability of SBT6050 and T-DXd 
• 
To further assess efficacy of SBT6050 and T-DXd 
 
 
 
 
 
 
 
 
 
Part 2: Phase 1 Dose Escalation Cohorts: 
Primary 
• 
To estimate the MTD, if reached, and determine the RP2D of SBT6050 when combined with tucatinib 
plus trastuzumab ± capecitabine 
• 
To evaluate the safety and tolerability of SBT6050 and tucatinib plus trastuzumab ± capecitabine 




 
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Study Population 
Inclusion Criteria: 
Subjects must meet all the following criteria to be enrolled in the study: 
1. Age 18 years or older 
2. a.) For Part 1, subjects must have locally advanced (unresectable) and/or metastatic human epidermal 
growth factor receptor 2 (HER2)-expressing or HER2-amplified cancer as noted below and previously 
received the following therapies (unless ineligible to receive or refused to receive or therapy is 
unavailable in the region): 
• 
Breast cancer (dose escalation cohorts [1a] and dose expansion Cohort A): HER2-positive 
expression (HER2pos) (immunohistochemistry [IHC] 3+ or IHC 2+/HER2 amplified) 
o 
≥1 prior lines of HER2-targeted therapy in the advanced setting and received taxane, 
trastuzumab, and pertuzumab in the early stage or advanced setting 
• 
Colorectal cancer (CRC; Kirsten rat sarcoma viral oncogene homolog gene [KRAS], neuroblastoma 
RAS viral [v-ras] oncogene homolog [NRAS], and v-raf murine sarcoma viral oncogene homolog 
B1 [BRAF] wild type) (dose escalation cohorts [1a] and dose expansion Cohort B): HER2pos (IHC 
3+ or IHC 2+/HER2 amplified) or HER2 amplified/IHC unknown 
o 
≥1 prior line of therapy and must have received chemotherapy with a fluoropyrimidine and 
oxaliplatin or irinotecan 
• 
Non-small-cell lung carcinoma (NSCLC) without targetable genetic alterations (eg, alterations of 
epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], ROS1, BRAF, 
mitogen-activated extracellular signal-regulated kinase [MEK], and neurotrophic tyrosine receptor 
kinase [NTRK], etc.) (dose escalation cohorts [1a] and dose expansion Cohort C): HER2-expressing 
(HER2exp) (IHC 3+ or IHC 2+) or HER2-amplified 
o 
≥1 prior line of therapy, which must include a platinum-based chemotherapy, and a 
programmed cell death-1 (PD 1)/programmed death-ligand 1 (PD-L1) inhibitor 
• 
Gastric or gastroesophageal junction (GEJ) cancer (dose escalation cohorts [1b] and dose expansion 
Cohort D): HER2pos (IHC 3+ or IHC 2+/HER2 amplified) 
o 
≥1 prior line of therapy and must have received a fluoropyrimidine, a platinum agent, and 
trastuzumab 
• 
Subjects in all Part 1 cohorts must not have received prior T-DXd for treatment of metastatic 
cancer 
b.) For Part 2, subjects must have locally advanced (unresectable) and/or metastatic HER2exp or 
HER2-amplified cancer as noted below and previously received the following therapies (unless 
ineligible to receive or refused to receive or therapy is unavailable in the region): 
• 
Breast cancer (dose escalation cohorts [2a] and dose expansion Cohorts E and G): HER2pos (IHC 3+ 
or IHC 2+/HER2 amplified) 
o 
≥1 prior line of HER2-targeted therapy in the advanced setting and received taxane, 
trastuzumab, and pertuzumab in either the early stage or advanced setting 
• 
CRC (KRAS, NRAS, and BRAF wild type) (dose escalation cohorts [2b] and dose expansion 
Cohort F): HER2pos (IHC 3+ or IHC 2+/HER2 amplified) or HER2 amplified/IHC unknown 
o 
≥1 prior line of therapy and must have received chemotherapy with fluoropyrimidine and 
oxaliplatin or irinotecan 
• 
Subjects in all Part 2 cohorts must not have received prior tucatinib for treatment of metastatic 
cancer 
3. Histologic confirmation of cancer and HER2 expression and/or amplification should be performed in a 
Clinical Laboratory Improvement Amendments (CLIA) (or local equivalent) certified laboratory: 
• 
Assessment of HER2 expression in subjects with breast and gastroesophageal cancer should follow 
guidelines published by the American Society of Clinical Oncology (ASCO), the College of 
American Pathologists (CAP), and the American Society for Clinical Pathologists (ASCP) 


 
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• 
If documentation of a previous HER2 result is not available, tumor tissue (archival tissue or slides 
or fresh tissue) or a blood sample must be submitted to a local CLIA-certified (or local equivalent) 
laboratory or a Sponsor-designated central laboratory to confirm HER2 expression and/or HER2 
amplification prior to enrollment 
4. Subjects must have a tumor lesion amenable for fresh biopsy, or be able to submit an adequate recent 
archived tumor tissue for baseline testing as follows; variations from tissue requirements must be 
discussed with the medical monitor: 
• 
Breast cancer and CRC: archival biopsy tissue obtained after the last HER2-directed therapy 
(excluding trastuzumab and pertuzumab), or a fresh biopsy 
• 
Gastric or GEJ cancer and NSCLC: archival biopsy tissue taken within the past 12 months and after 
completion of last HER2-directed therapy, or a fresh biopsy 
5. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. 
6. a) For Part 1, subjects must not have history of allergic reaction, including hypersensitivity reactions, to 
the following therapies: pertuzumab, trastuzumab, or T-DXd 
b.) For Part 2, subjects must not have history of allergic reaction, including hypersensitivity reactions, 
to the following therapies:  pertuzumab, tucatinib, trastuzumab, or capecitabine (for relevant cohorts) 
7. A brain magnetic resonance imaging (MRI) at baseline is required for 
• 
All subjects with breast cancer or NSCLC or 
• 
Subjects with gastric or GEJ cancer or CRC who have a history of central nervous system (CNS) 
metastases or have signs or symptoms suggestive of CNS metastases 
8. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Section 11.5) 
9. Adequate cardiac function with left ventricular ejection fraction (LVEF) ≥50% 
10. Adequate hematologic function, including: 
• 
Absolute neutrophil count (ANC) ≥1.5 × 109/L 
• 
Platelet count ≥100 × 109/L (platelet transfusions are not allowed within 1 week before screening 
visit) 
• 
Hemoglobin ≥9 g/dL (red blood cell transfusions are not allowed within 2 weeks before screening 
visit) 
11. Adequate blood clotting function with prothrombin time (PT) and activated partial thromboplastin 
time/partial thromboplastin time (aPTT/PTT) <1.5 × upper limit of normal (ULN) 
12. Adequate hepatic function with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 × ULN (if liver or bone metastases are present, ≤4 × ULN) and total bilirubin ≤1.5 × ULN or 
<3 × ULN in the presence of Gilbert’s syndrome 
13. Adequate renal function with estimated glomerular filtration rate (eGFR) ≥45 mL/minute based on 
Cockcroft-Gault equation (see Section 11.6) 
14. Female subjects of childbearing potential and fertile male subjects with partners who are of childbearing 
potential must agree to use highly effective contraception during the study and for up to 7 months (for 
females) or 2 months (for males) after the last dose of SBT6050 (see Section 11.7). 
Subjects must agree not to breastfeed, starting at the time of informed consent and continuing through 
7 months after the last dose of SBT6050 or 4 months after the last dose of T-DXd (Part 1) or tucatinib 
plus trastuzumab with or without capecitabine (Part 2), whichever is later. 
A female subject is considered of childbearing potential if she is anatomically and physiologically 
capable of becoming pregnant and will be or could possibly be sexually active with a male partner while 
undergoing study treatment with the possibility of posing harm to a fetus. 
A male subject is considered of sexual reproductive potential if he is anatomically and physiologically 
capable of causing a pregnancy in a female partner and will be or could possibly be sexually active with 
a female partner (who is or may become pregnant) while undergoing study treatment with the possibility 
of posing harm to a fetus. 
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monoclonal antibody (mAb) therapy at least 4 weeks prior to first dose of study treatment, and 
completing chemotherapy or therapy with small molecules at least 2 weeks prior to first dose of study 
treatment. Local radiation therapy must have been completed at least 2 weeks prior to the first dose of 
study treatment. 
16. The subject or the subject’s legally acceptable representative must provide written informed consent. 
Exclusion Criteria: 
Subjects who meet any of the following criteria will not be enrolled in the study: 
1. Prior lifetime exposure to anthracyclines exceeding: 
• 
Doxorubicin 360 mg/m2 
• 
Epirubicin 720 mg/m2 
• 
Mitoxantrone 120 mg/m2 
• 
Idarubicin 90 mg/m2 
• 
Liposomal doxorubicin 550 mg/m2 
2. Untreated brain metastases; subjects with treated brain metastases who are asymptomatic, have 
completed radiation therapy, and completed corticosteroid therapy at least 2 weeks prior to first dose of 
study treatment may participate 
3. Subjects requiring an equivalent of >10 mg/day of prednisone 
4. Active autoimmune disease or a documented history of autoimmune disease or syndrome that required 
systemic steroids (>10 mg/day prednisone or equivalent) or immunosuppressive agents within the past 
2 years. Subjects are permitted to enroll if they have vitiligo, type 1 diabetes, residual hypothyroidism 
due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic 
treatment, or resolved childhood asthma/atopy 
5. Uncontrolled or clinically significant renal, pancreas, or liver disease 
6. Subjects who are currently taking a medication which moderately induces cytochrome P450 family 2 
subfamily C (CYP2C), a medication which strongly inhibits cytochrome P450 family 2 subfamily C 
member 8 (CYP2C8), or if they are taking medications that interact with both enzymes: cytochrome 
P450 family 3 subfamily A (CYP3A) and CYP2C8 (see Section 11.8) 
7. Uncontrolled or clinically significant interstitial lung disease (ILD)/pneumonitis that required systemic 
corticosteroid (>10 mg prednisone per day or equivalent) treatment or suspected ILD/pneumonitis that 
cannot be ruled out by imaging at screening 
8. Positive for human immunodeficiency virus (HIV), hepatitis B (positive by surface antigen [HBsAg]), 
or hepatitis C infection (positive by ribonucleic acid polymerase chain reaction [HCV RNA PCR]) 
9. History of another primary invasive malignancy that has not been definitively treated and in remission 
for at least 1 year, except: 
a. 
Subjects with a history of prostate cancer (tumor/node/metastasis stage) of stage ≤T2cN0M0 
without biochemical recurrence or progression and who in the opinion of the Investigator are 
not deemed to require active intervention 
b. Subjects who have been adequately treated for a malignancy with a low potential risk for 
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10. History of symptomatic congestive heart failure (New York Heart Association classes II–IV), unstable 
angina, myocardial infarction, serious cardiac arrhythmia, or cerebral vascular accident within 6 months 
prior to first dose of study treatment 
11. Corrected QT interval using Fridericia’s formula (QTcF) >470 msec (females) or >450 msec (males) 
12. Other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, 
would either compromise the subject’s safety or interfere with the evaluation of the safety of the study 
treatment 
13. Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of informed 
consent until 7 months after final dose of SBT6050 or 4 months after final dose of T-DXd (Part 1) or 
tucatinib plus trastuzumab with or without capecitabine (Part 2), whichever is later 
14. Life expectancy ≤3 months, in the opinion of the Investigator 
Number of Planned Subjects 
Up to approximately 328 subjects will be enrolled across this 2-part study. Up to approximately 184 people will 
be enrolled in Part 1 and up to approximately 144 people will be enrolled in Part 2. 
Study Design 
This is a phase 1/2 open-label, multicenter, dose-escalation and expansion study designed to evaluate the safety, 
tolerability, PK, pharmacodynamics, immunogenicity, and efficacy of SBT6050 in combination with T-DXd 
(Part 1) or tucatinib and trastuzumab ± capecitabine (Part 2). 
The study is designed to determine the MTD, if reached, of SBT6050 when combined with two dose levels of 
T-DXd (Part 1) or with tucatinib and trastuzumab ± capecitabine (Part 2). In dose escalation, two dose levels of 
SBT6050 are planned (0.45 mg/kg and 0.6 mg/kg). The MTD is defined as the dose just below the dose level 
with at least 2 out of 6 subjects (≥33%) experiencing dose-limiting toxicities (DLTs). The DLT evaluation period 
is 21 days. 
Dose expansion will be initiated once the Safety Monitoring Committee (SMC) has determined the SBT6050 
RP2D from dose escalation of each respective part. The SBT6050 RP2D may be different for each of the four 
regimens. Dose expansion cohorts are designed to confirm the safety and tolerability of the RP2D for each 
combination regimen and to evaluate efficacy and pharmacodynamic effects of SBT6050 when combined with T-
DXd (Part 1) or tucatinib and trastuzumab ± capecitabine (Part 2). Subjects will be enrolled into parallel 
expansion cohorts based on tumor type and HER2 expression level. Throughout dose expansion, the Sponsor will 
continually monitor safety data to assess benefit versus risk for subjects. 
Investigational Product, Dose, and Mode of Administration 
SBT6050 will be administered via subcutaneous (SC) injection as a single dose administered every 21 days 
(every 3 weeks [Q3W]). SBT6050 should not be administered as an intravenous (IV) bolus or infusion. Refer to 
the Pharmacy Manual for detailed instructions regarding SC administration of SBT6050. 
In both Part 1 and Part 2, during dose escalation, the starting dose of SBT6050 is 0.45 mg/kg and the next dose 
level is 0.6 mg/kg. 
In both Part 1 and Part 2, the SBT6050 RP2D for subjects during dose expansion will be determined based on 
safety, PK, pharmacodynamic, and clinical activity results from dose escalation. 






 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................................................ 21 
1.1 
Background ........................................................................................................................................... 22 
1.1.1 
HER2-expressing Cancer ...................................................................................................................... 22 
1.1.2 
Therapeutic Options for HER-expressing Cancer................................................................................. 22 
1.2 
Study Treatments .................................................................................................................................. 25 
1.2.1 
SBT6050 ............................................................................................................................................... 25 
1.2.2 
Trastuzumab Deruxtecan ...................................................................................................................... 28 
1.2.3 
Tucatinib ............................................................................................................................................... 29 
1.2.4 
Trastuzumab ......................................................................................................................................... 30 
1.2.5 
Capecitabine ......................................................................................................................................... 31 
1.3 
Study Rationale ..................................................................................................................................... 31 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 33 
2.1.1 
Part 1: SBT6050 Combined With Trastuzumab Deruxtecan ................................................................ 33 
2.1.2 
Part 2: SBT6050 Combined With Tucatinib and Trastuzumab ± Capecitabine ................................... 35 
3. 
INVESTIGATIONAL PLAN ............................................................................................................... 37 
3.1 
Summary of Study Design .................................................................................................................... 37 
3.1.1 
Part 1: SBT6050 Combined With Trastuzumab Deruxtecan ................................................................ 38 
3.1.2 
Part 2: SBT6050 Combined With Tucatinib and Trastuzumab With or Without Capecitabine ........... 39 
3.1.3 
Dose Escalation .................................................................................................................................... 39 
3.1.4 
Replacement of Subjects ....................................................................................................................... 42 
3.1.5 
End of Study ......................................................................................................................................... 42 
4. 
STUDY POPULATION ....................................................................................................................... 43 
4.1 
Inclusion Criteria .................................................................................................................................. 43 
4.2 
Exclusion Criteria ................................................................................................................................. 46 
4.3 
Criteria for Discontinuation from Study Treatment and Withdrawal of Subjects ................................. 47 
4.3.1 
Discontinuation of Study Treatment ..................................................................................................... 47 
4.3.2 
Discontinuation From the Study ........................................................................................................... 48 
5. 
STUDY TREATMENTS ...................................................................................................................... 49 
5.1 
Treatments Administered ...................................................................................................................... 49 
5.2 
Investigational Product: SBT6050 ........................................................................................................ 49 
5.2.1 
Description of SBT6050 ....................................................................................................................... 50 
5.2.2 
Dose and Administration of SBT6050 .................................................................................................. 50 
5.2.3 
Storage and Handling of SBT6050 ....................................................................................................... 50 
5.2.4 
Packaging and Labeling of SBT6050 ................................................................................................... 51 
5.2.5 
Preparation of SBT6050 ....................................................................................................................... 51 
5.3 
Part 1: SBT6050 Combined With Trastuzumab Deruxtecan ................................................................ 51 


 
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5.4 
Part 2: SBT6050 Combined With Tucatinib and Trastuzumab ± Capecitabine ................................... 51 
5.4.1 
Tucatinib ............................................................................................................................................... 51 
5.4.2 
Trastuzumab ......................................................................................................................................... 51 
5.4.3 
Capecitabine ......................................................................................................................................... 52 
5.5 
Concomitant Medications ..................................................................................................................... 52 
5.5.1 
Required Premedication and Postmedication ....................................................................................... 52 
5.5.2 
Recommended Supportive Medications ............................................................................................... 53 
5.5.3 
Allowed Concomitant Therapy ............................................................................................................. 53 
5.5.4 
Prohibited Concomitant Therapy .......................................................................................................... 54 
5.6 
Dose Modifications ............................................................................................................................... 54 
5.6.1 
Dose Modifications for SBT6050 and T-DXd ...................................................................................... 54 
5.6.2 
Dose Modifications for Tucatinib plus Trastuzumab ± Capecitabine ................................................... 58 
5.7 
Management of Overdose ..................................................................................................................... 61 
5.8 
Treatment Compliance .......................................................................................................................... 61 
5.9 
Study Drug Accountability ................................................................................................................... 61 
6. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................................ 62 
6.1 
Screening/Baseline Procedures ............................................................................................................. 62 
6.2 
Efficacy Measurements......................................................................................................................... 63 
6.3 
Pharmacokinetic Measurements ........................................................................................................... 63 
 
 
 
 
 
 
 
 
6.4.4 
Immunogenicity Measurements ............................................................................................................ 65 
 
 
6.6 
Safety Assessments on Cycle 1, Day 1 and Beyond ............................................................................. 66 
6.6.1 
Physical Examination ........................................................................................................................... 66 
6.6.2 
Pregnancy Testing ................................................................................................................................ 66 
6.6.3 
Vital Signs ............................................................................................................................................ 66 
6.6.4 
12-Lead Electrocardiogram .................................................................................................................. 66 
6.6.5 
Echocardiogram or Multigated Acquisition Scan ................................................................................. 66 
6.6.6 
Eastern Cooperative Oncology Group Performance Status .................................................................. 67 
6.6.7 
Oxygen Saturation ................................................................................................................................ 67 
6.6.8 
Clinical Laboratory Tests ...................................................................................................................... 67 
6.7 
Long-term Follow-up (Every 3 Months After 30-day Follow-up Visit) ............................................... 67 
6.8 
End of Study/End of Follow-up ............................................................................................................ 67 
6.9 
Adverse Events ..................................................................................................................................... 68 


 
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6.9.1 
Definitions ............................................................................................................................................ 68 
6.9.2 
Procedures for Eliciting and Recording Adverse Events ...................................................................... 70 
6.9.3 
Abnormal Laboratory Values ............................................................................................................... 72 
6.9.4 
Reporting Periods for Adverse Events and Serious Adverse Events .................................................... 73 
6.9.5 
Serious Adverse Events Require Immediate Reporting ........................................................................ 73 
6.9.6 
Sponsor Safety Reporting to Regulatory Authorities ............................................................................ 74 
6.10 
Appropriateness of Measurements ........................................................................................................ 74 
7. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 75 
7.1 
Site Training and Monitoring Procedures ............................................................................................. 75 
7.2 
Data Management Procedures .............................................................................................................. 75 
7.3 
Access to Source Data .......................................................................................................................... 75 
7.4 
Accuracy and Reliability of Data .......................................................................................................... 76 
7.5 
Quality Assurance Procedures .............................................................................................................. 76 
7.6 
Data Handling and Record Keeping ..................................................................................................... 76 
7.6.1 
Data Handling ....................................................................................................................................... 76 
7.6.2 
Investigator Record Retention .............................................................................................................. 76 
8. 
STATISTICAL CONSIDERATIONS .................................................................................................. 77 
8.1 
Determination of Sample Size .............................................................................................................. 77 
8.2 
Analysis Populations ............................................................................................................................ 79 
8.3 
Efficacy Analyses ................................................................................................................................. 79 
8.3.1 
Dose Expansion Cohorts ....................................................................................................................... 79 
8.4 
Safety Analyses .................................................................................................................................... 80 
8.5 
Pharmacokinetic Analyses .................................................................................................................... 80 
8.6 
Pharmacodynamic Analyses ................................................................................................................. 80 
8.7 
Timing of Analysis ............................................................................................................................... 80 
8.7.1 
Interim Analyses ................................................................................................................................... 81 
9. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS ............................................................................................................................ 82 
9.1 
Informed Consent ................................................................................................................................. 82 
9.2 
Ethical Review ...................................................................................................................................... 82 
9.3 
Regulatory Considerations .................................................................................................................... 82 
9.3.1 
Investigator Information ....................................................................................................................... 82 
9.3.2 
Protocol Amendments and Study Termination ..................................................................................... 83 
9.4 
Study Documentation, Privacy, and Records Retention ....................................................................... 83 
10. 
REFERENCES ..................................................................................................................................... 84 
11. 
APPENDICES ...................................................................................................................................... 89 
11.1 
Schedule of Assessments for Part 1: SBT6050 Combined With Trastuzumab Deruxtecan ................. 90 


 
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11.2 
Schedule of Assessments for Part 2: SBT6050 Combined With Tucatinib Plus Trastuzumab 
With or Without Capecitabine .............................................................................................................. 93 
11.3 
Common Terminology Criteria for Adverse Events ............................................................................. 96 
11.4 
Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 ............................................... 97 
11.5 
Eastern Cooperative Oncology Group Performance Status ................................................................ 100 
11.6 
Cockroft-Gault Equation ..................................................................................................................... 101 
11.7 
Guidance on Contraception ................................................................................................................ 102 
11.8 
Drug Interactions Table of Substrates, Inhibitors, and Inducers ......................................................... 103 
11.9 
Investigator Statement ........................................................................................................................ 104 
11.10 
Document History ............................................................................................................................... 105 
 
LIST OF TABLES 
Table 1: 
Recommended SBT6050 dose levels .................................................................................................... 50 
Table 2: 
T-DXd dose reduction schedule............................................................................................................ 55 
Table 3: 
Recommended dose modifications for SBT6050 and T-DXd .............................................................. 56 
Table 4: 
Tucatinib dose reduction schedule ........................................................................................................ 58 
Table 5: 
Recommended dose modifications for SBT6050, tucatinib, trastuzumab, and capecitabine ................ 59 
Table 6: 
Historical and target ORR estimates with associated precision and power calculations under 
varying response probabilities for SBT6050 combined with T-DXd ................................................... 78 
Table 7: 
Historical and target ORR estimates with associated precision and power calculations under 
varying response probabilities for SBT6050 combined with tucatinib and trastuzumab ± 
capecitabine .......................................................................................................................................... 78 
 
LIST OF FIGURES 
Figure 1: Overall Study Schema .................................................................................................................................. 38 
 


 
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT A01 
Section(s) 
Change 
Rationale 
Synopsis, Figure 1, 
3.1.1.1, 3.1.1.2, 4.1, 
5.1, 5.3 
Treatment with T-DXd for subjects with NSCLC lowered from 6.4 mg/kg to 
5.4 mg/kg. 
To update the dose of T-DXd in NSCLC. 
Synopsis, 4.1, Table 6 
Cohort C (NSCLC) and Cohort D (gastric or GEJ cancer) revised to reflect 
the appropriate population description. 
Correction. 
1.1.2.3, Table 6 
Updated confirmed response results from the recently published DESTINY-
Gastric02 study. 
To reflect the updated response rates for the 
combination therapy. 
3.1.3 
Removed reference to the Sponsor being part of the voting members of the 
ILD Adjudication Committee 
Correction. 
5.4.1 
Added the following statement for tucatinib dose and administration: 
Tucatinib should be taken after administration of SBT6050 and trastuzumab 
in the clinic on Cycle 1 Day 1. On Day 1 of each subsequent cycle, study staff 
should review tucatinib compliance from previous cycle. 
Clarification. 
5.4.3 
Added the following statement for capecitabine dose and administration: 
Capecitabine should be taken after administration of SBT6050 and 
trastuzumab in the clinic on Cycle 1 Day 1. On Day 1 of each subsequent 
cycle, study staff should review capecitabine compliance from previous cycle. 
Clarification. 
5.5.1 
Added the following language regarding required premedications: 
In Part 1, subjects are required to receive 
• 
Ondansetron (or equivalent) 16 mg IV once at least 30 minutes prior to 
the dose of SBT6050 and then 8 mg PO every 8 hours as needed (PRN) 
for nausea and/or vomiting starting 8 hours after the prior dose of 
ondansetron 
• 
Dexamethasone (or equivalent) 8 mg PO every day for 3 days, beginning 
the day prior to Day 1 of each cycle, on Day 1 of each cycle at least 30-
60 minutes prior to SBT6050 dosing, and ending on Day 2 of each cycle 
In Part 2, subjects are required to receive 
• 
Dexamethasone (or equivalent) 8 mg PO on Day 1 of each cycle at least 
30-60 minutes prior to SBT6050 dosing 
• 
Ondansetron (or equivalent) 8 mg PO every 8 hours PRN for nausea 
and/or vomiting 
To better conform with standard oncology 
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Section(s) 
Change 
Rationale 
5.5.2 
Added the following language regarding recommended supportive 
medications: 
• 
Systemic corticosteroid as needed to treat ≥Grade 3 hypotension (not 
responding to IV fluid infusion), or ≥Grade 3 hypoxia, or ≥Grade 2 CRS, 
such as 
o 
methylprednisolone 1 mg/kg IV or equivalent, given as a single dose  
o 
dexamethasone 8-12 mg IV/PO given as a single dose 
To better conform with standard oncology 
premedication regimens. 
Table 2 
Revised table column headings to reflect dose level rather than disease 
diagnosis for T-DXd dose reductions. 
Correction. 
6.4.3 
Added the following language to skin biopsies: 
Photographs of the subject’s injection site in the abdomen and the 
surrounding body areas may be taken by the study staff to assess any side 
effects. The photographs are for research purposes only and will be de-
identified. 
To allow for collection of photographs of subjects 
in the event of a skin reaction. 
6.6.5, 11.1, 11.2 
Added language to ECHO/MUGA scans stating that they will be obtained 
every 12 weeks as determined from Cycle 1 Day 1. 
Clarification. 
 
 
 
11.1, 11.2 
Added the following to footnote “f”: 
Creatinine clearance, only required for eligibility criteria at 
Screening/Baseline, will be calculated using the Cockcroft-Gault formula. 
Clarification. 
11.2 
Revised the footnote for treatments to be administered during the study in 
Part 2 to include trastuzumab. 
Clarification. 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
5-FU 
fluorouracil 
5-FU/LV 
fluorouracil plus leucovorin 
ADA 
antidrug antibody 
ADC 
antibody-drug conjugate 
ADCC 
antibody-dependent cell mediated cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology  
ASCP 
American Society for Clinical Pathologists 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BID 
twice daily 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CLIA 
Clinical Laboratory Improvement Amendments 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
  
 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
Ctrough 
trough concentration 
CV 
coefficient of variation 


 
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Abbreviation 
Definition 
CYP2C 
cytochrome P450 family 2 subfamily C 
CYP2C8 
cytochrome P450 family 2 subfamily C member 8 
CYP3A 
cytochrome P450 family 3 subfamily A 
DC 
dendritic cell 
DLT 
dose-limiting toxicity 
dMMR 
deficient mismatch repair 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
eCRF 
electronic case report form 
EU 
European Union 
 
 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FOLFIRI 
fluorouracil, leucovorin, and irinotecan 
FOLFOX 
fluorouracil, leucovorin, and oxaliplatin 
FT3 
free tri-iodothyronine 
FT4 
free thyroxine 
GEJ 
gastroesophageal junction 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HER2exp 
human epidermal growth factor receptor 2 expression 
HER2pos 
human epidermal growth factor receptor 2 positive expression 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
independent ethics committee 


 
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Abbreviation 
Definition 
IFN 
interferon 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
institutional review board 
ISH 
in situ hybridization 
ISR 
injection site reaction 
IUD 
intrauterine device 
IV 
intravenous 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LVEF 
left ventricular ejection fraction 
LTFU 
long-term follow-up 
mAb 
monoclonal antibody 
MCP 
monocyte chemoattractant protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen-activated extracellular signal-regulated kinase pathway 
MIP 
macrophage inflammatory protein 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition 
NCI 
National Cancer Institute 
 
 
NK 
natural killer 
NOAEL 
no observed adverse effect level 
NRAS 
neuroblastoma RAS viral [v-ras] oncogene homolog 
NSCLC 
non-small cell lung carcinoma 
NTRK 
neurotrophic tyrosine receptor kinase 
ORR 
objective response rate 
OR 
objective response 
OS 
overall survival 
 
 
PCR 
polymerase chain reaction 
PD-1 
programmed cell death-1 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 


 
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Abbreviation 
Definition 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
by mouth (orally) 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTcF 
corrected QT interval using Fridericia’s formula 
QW 
every week 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
RAS 
rat sarcoma viral oncogene homolog 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
ROS1 
receptor tyrosine kinas encoded by the gene ROS1 
RP2D 
recommended phase 2 dose 
RR 
response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
stable disease 
SIRPα 
signal-regulatory protein alpha 
SMC 
Safety Monitoring Committee 
SUSAR 
suspected unexpected serious adverse reactions 
T3 
tri-iodothyroinine 
t1/2 
apparent terminal half-life 
tAb 
total antibody 
T-DM1 
trastuzumab emtansine 
T-DXd 
trastuzumab deruxtecan 
TEAE 
treatment-emergent adverse event 
TLR8 
toll-like receptor 8 
Tmax 
time to maximum concentration 
 
 
TNFα 
tumor necrosis factor alpha 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 


 
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Abbreviation 
Definition 
US 
United States 
USPI 
United States Prescribing Information 
VEGF 
vascular endothelial growth factor 


 
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1. INTRODUCTION 
SBT6050 is a novel therapeutic comprising a selective small molecule toll-like receptor 8 
(TLR8) agonist linked to the HER2-directed monoclonal antibody (mAb) pertuzumab, allowing 
for combination with trastuzumab-based agents and regimens. SBT6050 is designed to activate 
myeloid cells in tumors expressing moderate to high levels of HER2. TLR8 agonism directly 
activates myeloid cells, including macrophages and dendritic cells (DCs), and secondarily 
activates natural killer (NK) and T cells, inducing a broad spectrum of antitumor immune 
mechanisms. SBT6050 is currently being tested as a single agent and in combination with 
programmed cell death-1 (PD-1) inhibitors (NCT04460456). SBT6050 was well tolerated at a 
dose of 0.6 mg/kg, induced cytokines indicating myeloid cell and NK/T cell activation, and 
demonstrated early signs of antitumor activity. 
Trastuzumab deruxtecan (T-DXd) (ENHERTU 2021) is an antibody-drug conjugate (ADC) 
composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I 
inhibitor. T-DXd has demonstrated favorable outcomes in patients with previously treated 
HER2-expressing (HER2exp) solid tumors, including breast cancer, gastric/gastroesophageal 
junction (GEJ) cancer, colorectal cancer (CRC), and non-small-cell lung carcinoma (NSCLC), 
leading to multiple regulatory approvals in the United States (US) and other regions. T-DXd is 
generally well tolerated; adverse events (AEs) of note include interstitial lung disease (ILD) and 
neutropenia, which may require dose interruption or reduction. 
Tucatinib (TUKYSA 2020) is a potent and selective oral HER2 inhibitor that has recently 
received regulatory approval in the US and other regions based on improved progression-free 
survival (PFS) and overall survival (OS) in patients with previously treated HER2-positive 
(HER2pos) breast cancer, when given in combination with trastuzumab and capecitabine. 
Improved outcomes were also observed in the subset of patients with breast cancer and a history 
of brain metastases, a challenging treatment setting with few options. Additionally, tucatinib plus 
trastuzumab in patients with HER2pos CRC has demonstrated encouraging results, with a 
substantial rate of durable responses. Tucatinib and trastuzumab with or without (±) 
capecitabine, is well tolerated with significant AEs including diarrhea and hepatotoxicity, which 
may require dose reductions or interruptions. 
Strong scientific rationale supports the combination of SBT6050 with either T-DXd or 
trastuzumab plus tucatinib ± capecitabine. Both treatment regimens drive immunogenic tumor 
cell death and release of tumor neoantigens. SBT6050 can enhance tumor neoantigen 
presentation and subsequent activation of T cell responses through its direct activation of DCs. 
Thus, SBT6050 combined with T-DXd or trastuzumab plus tucatinib ± capecitabine is postulated 
to drive broad antitumor T cell responses. SBT6050 enhances the antibody-dependent cell 
mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) supported 
by trastuzumab and T-DXd. SBT6050 activates myeloid cells to secrete cytokines that amplify 
ADCC by NK cells. Additionally, SBT6050 activation downmodulates signal-regulatory protein 
alpha (SIRPα) on the surface of myeloid cells, which increases ADCP through attenuation of the 
CD47-SIRPα interaction. Consistent with this, in preclinical studies in mice, the combination of 
trastuzumab and a mouse surrogate of SBT6050 led to enhanced activity in the HER2pos 
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1.1 Background 
1.1.1 HER2-expressing Cancer 
HER2 is an oncogenic driver and established therapeutic target in breast and gastric/GEJ cancers. 
HER2 overexpression or amplification has been reported in approximately 20% of breast and 
gastric/GEJ cancers and is also described in NSCLC, CRC, and multiple other tumor types. 
Guidelines for clinical testing for HER2 overexpression using Food and Drug Administration 
(FDA)-approved diagnostic tests have been established in breast and gastric/GEJ tumors 
(Ruschoff 2012) (Wolff 2013). Similar methods have been used to screen for HER2 expression 
in clinical trials for patients with CRC and NSCLC (Valtorta 2015) (Doi 2017) (Shen 2019). 
HER2 overexpression refers to detection of the HER2 protein by immunohistochemistry (IHC). 
HER2 gene amplification is detected by in situ hybridization (ISH), differential polymerase 
chain reaction (PCR), or next-generation sequencing (NGS). Breast and gastric cancer are 
defined as HER2pos if they are either IHC 3+ or IHC 2+ and gene amplified. Similar terminology 
has been applied in clinical trials for patients with CRC and NSCLC. 
1.1.2 Therapeutic Options for HER-expressing Cancer 
HER2 is a validated target for treatment of advanced cancers, and several HER2-directed 
therapies have obtained regulatory approval in the US and globally. However, most patients with 
advanced HER2pos-solid tumors eventually relapse and require additional therapeutic options. 
1.1.2.1 HER2pos Metastatic Breast Cancer 
Trastuzumab plus pertuzumab in combination with a taxane is the standard-of-care first-line 
therapy for patients with HER2pos metastatic breast cancer, increasing the time to progression 
and OS (Slamon 2001) (Baselga 2012). HER2 overexpression persists and remains relevant 
beyond progression, and strategies to overcome resistance have been developed; for example, 
changing the HER2-directed agent or switching chemotherapies in subsequent lines of treatment. 
Trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) comprising the cytotoxic 
agent DM1 linked to trastuzumab, has demonstrated positive outcomes (PFS; median, 
6.2 months versus 3.3 months; hazard ratio [HR] 0.53, 95% confidence interval (CI) 0.42–0.66, 
and OS; median, 22.7 versus 15.8 months; HR 0.68, 95% CI 0.54–0.85 ) in patients with 
HER2pos breast cancer previously treated with trastuzumab and a taxane, and is a standard-of-
care second-line therapy for metastatic breast cancer (Verma 2012) (Krop 2014) (Robert 2006) 
(Pegram 2004). 
Tucatinib plus trastuzumab and capecitabine demonstrated improved PFS (median 7.8 months 
versus 5.6 months) and OS (median 21.9 months versus 17.4 months) compared to trastuzumab 
and capecitabine alone in patients with metastatic breast cancer who had received prior therapy 
and has received regulatory approval in multiple regions. Tucatinib plus trastuzumab and 
capecitabine has also demonstrated both a PFS benefit (9.9 months versus 4.2 months; HR 0.32, 
95% CI 0.22–0.48 and a survival benefit (18 months versus 12 months; HR 0.58, 95% CI 0.40–
0.85) in patients with central nervous system (CNS) metastases (Murthy 2020). 


 
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T-DXd recently demonstrated strong activity in a single arm study, with an objective response 
rate (ORR) of 61%, duration of response (DOR) of 14.8 months, and PFS of 16.4 months in 
patients with HER2pos metastatic breast cancer who had received prior therapies (Modi 2020). 
Results from this study resulted in accelerated and conditional approval in the US and the 
European Union (EU), respectively, for treatment of patients with HER2pos metastatic breast 
cancer who have received two or more prior HER2-directed therapies. T-DXd is also approved 
in Japan under accelerated approval in patients with HER2pos unresectable or recurrent metastatic 
breast cancer who have received prior chemotherapy and are refractory or intolerant to standard 
treatments. Recently, it was reported that a phase 3 study comparing T-DXd to T-DM1 in 
patients with HER2pos breast cancer who have received one prior therapy for metastatic disease 
met the primary endpoint of PFS, with T-DXd demonstrating superiority over T-DM1 
(Astrazeneca 2021). 
1.1.2.2 HER2pos Colorectal Cancer 
HER2 is overexpressed in 6–10% of patients with CRC and is often associated with gene 
amplification (Valtorta 2015) (Ross 2018) (Siena 2021). Regardless of HER2 status, standard of 
care first-line therapy for locally advanced, recurrent, or metastatic CRC is FOLFOX 
(fluorouracil [5-FU], leucovorin and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan), 
depending on prior adjuvant therapy regimens. FOLFOX and FOLFIRI are given with or without 
bevacizumab (vascular endothelial growth factor [VEGF] inhibitor), or with or without 
cetuximab or panitumumab (epidermal growth factor receptor [EGFR] inhibitor) if the tumor is 
wild-type for Kirsten rat sarcoma viral oncogene homolog gene (KRAS)/neuroblastoma RAS 
viral (v-ras) oncogene homolog (NRAS)/v-raf murine sarcoma viral oncogene homolog B1 
(BRAF). Capecitabine is sometimes substituted for 5-FU. For patients who cannot tolerate 
intensive chemotherapy, oxaliplatin or irinotecan may be omitted. Other options include 
nivolumab with or without ipilimumab or pembrolizumab for patients with tumors that are 
deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H), and encorafenib plus 
cetuximab or panitumumab for patients with tumors that are BRAFV600E-mutation positive. 
A meta-analysis of 11 clinical trials analyzed the efficacy of FOLFIRI-bevacizumab as second-
line chemotherapy in advanced CRC patients pretreated with oxaliplatin and not with 
bevacizumab. Overall, the pooled response rate (RR) (N=11 publications) was 26 %. Median 
PFS and OS (n=11 and 10 publications, respectively) were 8.3 months and 17.2 months. Studies 
of FOLFIRI alone in the second line setting demonstrated a PFS range of 3.4–11.2 months 
(Guiducci 2013) (Beretta 2013). 
Although the standard recommendation for second-line therapy for metastatic CRC is additional 
chemotherapy, HER2-directed therapy may be an option for patients with HER2pos CRC. 
A phase 2 study demonstrated promising activity of HER2-targeted therapy with trastuzumab 
and lapatinib in CRC (Sartore-Bianchi 2016), with an ORR of 30% (95% CI 14, 50) and a DOR 
of 38 weeks (95% CI 24–94+). 
Pertuzumab plus trastuzumab was evaluated as part of the phase 2a multicenter multiple basket 
study exploring targeted therapies with potentially predictive molecular alterations. In a cohort 
comprising 57 patients with treatment-refractory histologically confirmed HER2-amplified 
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combination pertuzumab and trastuzumab, with one patient (2%) achieving complete response 
(CR), and the regimen was well tolerated (Meric-Bernstam 2019). 
T-DXd showed promising and durable activity in patients with HER2pos metastatic CRC 
refractory to standard treatment, with a safety profile consistent with that reported in previous 
T-DXd trials. In the recently published interim results of the DESTINY-CRC01 phase 2 trial, for 
the 53 patients (68%) with HER2pos tumors (cohort A), a confirmed objective response (OR) was 
reported in 24 patients (45.3%, 95% CI 31.6–59.6) with a median DOR of 7 months (95% CI 
5.8–9.5) (Yoshino 2021). 
An open-label, phase 2 study of trastuzumab plus tucatinib for patients with rat sarcoma viral 
oncogene homolog (RAS) wild type metastatic CRC in second-line and beyond is ongoing. 
Initial results in 45 patients have shown an ORR of 52%, median PFS of 8.1 months and OS of 
18.7 months (Strickler 2021). An additional 70 patients were randomized in a 4:3 manner 
into 2cohorts (trastuzumab plus tucatinib or tucatinib alone, with the option to crossover to 
trastuzumab plus tucatinib). 
Other available agents include regorafenib and trifluridine plus tipiracil and are associated with a 
PFS of approximately 2 months. 
1.1.2.3 HER2pos Metastatic Gastric/GEJ Cancer 
The treatment landscape for HER2pos gastric/GEJ cancer is rapidly changing. Trastuzumab in 
combination with FOLFOX is the established front-line standard of care in HER2pos, locally 
advanced, recurrent or metastatic gastric/GEJ tumors based on OS benefit demonstrated in a 
phase 3 study (Bang 2010). 5FU-combination therapy with cisplatin or irinotecan may also be 
utilized in the first-line metastatic gastric/GEJ cancer population. Capecitabine can be 
interchanged for 5FU/LV (fluorouracil plus leucovorin), except when irinotecan is part of the 
regimen. 
Recently, an interim analysis from a phase 3 randomized study comparing the addition of 
pembrolizumab versus placebo to trastuzumab plus chemotherapy in front-line therapy for 
patients with HER2pos metastatic gastric/GEJ cancer (KEYNOTE 811) demonstrated an ORR of 
74% (DOR of 10.5 months) for the pembrolizumab arm versus an ORR of 52% (DOR of 
9.5 months) for the placebo arm. Pembrolizumab was granted FDA accelerated approval in the 
US for this indication, pending final analysis of the primary endpoint (PFS/OS). 
Standard of care in the second line or beyond for HER2pos metastatic gastric/GEJ cancer depends 
on prior therapy and performance status. Ramucirumab and paclitaxel are commonly used, with 
a response rate of approximately 10–30% and PFS of approximately 3–4 months (Wilke 2014) 
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• 
 
 
 
 
 
 
 
 
 
A more detailed summary of the nonclinical and clinical SBT6050 safety data is provided in the 
Investigator’s Brochure. 
1.2.2 Trastuzumab Deruxtecan 
Trastuzumab deruxtecan (ENHERTU®) is a HER2-directed antibody and topoisomerase I 
inhibitor-drug conjugate with excellent response rates in multiple HER2exp malignancies. T-DXd 
has recently received regulatory approval in multiple regions to treat patients diagnosed with 
HER2pos metastatic breast cancer who have received two or more prior HER2 -directed therapies 
and in patients with HER2pos gastric/GEJ cancer who have received trastuzumab-based therapy 
in gastric cancer (US) and in patients with HER2pos unresectable advanced or recurrent gastric 
cancer that has progressed after chemotherapy (Japan). T-DXd has also demonstrated 
encouraging preliminary activity in patients with HER2exp NSCLC and HER2pos CRC. 
Identified safety risks as described in the regional labeling for T-DXd are (ENHERTU 2021): 
• Interstitial lung disease(ILD)/pneumonitis: ILD occurred in 9% of patients with breast 
cancer treated with T-DXd at 5.4 mg/kg. Fatal outcomes due to ILD and/or pneumonitis 
occurred in 2.6% of patients. Median time to first onset was 4.1 months. ILD occurred in 
10% of patients with gastric/GEJ cancer treated with T-DXd at 6.4 mg/kg. Median time 
to first onset was 2.8 months. 
• Hematologic toxicity: Among patients with breast cancer treated with T-DXd at 
5.4 mg/kg, 62% of patients had a decrease in neutrophil count (16% Grade 3–4). Febrile 
neutropenia was reported in 1.7% of patients. Among patients with gastric/GEJ cancer 
treated with T-DXd at 6.4 mg/kg, 72% of patients had a decrease in neutrophil count 
(51% Grade 3–4). Febrile neutropenia was reported in 4.8% of patients. 
• Left ventricular dysfunction: Among patients with breast cancer treated with T-DXd at 
5.4 mg/kg, 0.9% of patients developed an asymptomatic decrease in LVEF. Among 
patients with gastric/GEJ cancer treated with T-DXd at 6.4 mg/kg, no clinical AEs of 
heart failure were reported; however, on echocardiography, 8% were found to have 
asymptomatic Grade 2 decrease in left ventricular ejection fraction (LVEF). 
• Embryo-fetal toxicity: Based on its mechanism of action, T-DXd can cause fetal harm 
when administered to a pregnant woman. In post marketing reports, use of a HER2-
directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as 
fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on its 
mechanism of action, the topoisomerase inhibitor component of T-DXd, deruxtecan, can 
also cause embryo-fetal harm when administered to a pregnant woman because it is 
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1.2.3 Tucatinib 
Tucatinib (TUKYSA®) is a small molecule inhibitor of HER2 for the treatment of HER2pos 
breast cancer. Tucatinib received approval in the US in combination with trastuzumab and 
capecitabine for the treatment of adults with locally-advanced, unresectable or metastatic 
HER2pos breast cancer, including those with brain metastases, who have received one or more 
prior anti-HER2-based regimens in the metastatic setting. 
Tucatinib plus trastuzumab ± capecitabine 
In 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the 
treatment of patients with advanced, unresectable or metastatic HER2pos breast cancer, who had 
previously been treated with trastuzumab, pertuzumab (PERJETA®), and trastuzumab emtansine 
(KADCYLA®), based on the results of the HER2CLIMB study. 
The median PFS in subjects who received tucatinib plus trastuzumab and capecitabine was 
7.8 months (95% CI: 7.5, 9.6) compared to 5.6 months (95% CI: 4.2, 7.1) in those subjects who 
received placebo plus trastuzumab and capecitabine (HR 0.54; 95% CI: 0.42, 0.71; P<0.00001). 
The median OS in subjects who received tucatinib plus trastuzumab and capecitabine was 
21.9 months (95% CI: 18.3, 31.0) compared to 17.4 months (95% CI: 13.6, 19.9) in subjects who 
received placebo plus trastuzumab and capecitabine (HR: 0.66; 95% CI: 0.50, 0.87; P=0.00480). 
The median PFS in subjects with brain metastases at baseline who received tucatinib plus 
trastuzumab and capecitabine was 7.6 months (95% CI: 6.2, 9.5) compared to 5.4 months (95% 
CI: 4.1, 5.7) in subjects who received placebo plus trastuzumab and capecitabine (HR: 0.48; 
0.34, 0.69; P<0.00001) (Murthy 2020). 
Tucatinib and trastuzumab has also been studied in patients with HER2pos, RAS wild-type 
metastatic CRC who have progressed on first- and second-line therapy with FOLFOX and 
FOLFIRI. In the phase 1 MOUNTAINEER01 trial, the results were ORR 52%, PFS 8.1 months, 
OS 18.7 months, and DOR 10.4 months (Strickler 2021). 
Identified safety risks as described in the regional labeling for tucatinib are (TUKYSA 2020): 
• Gastrointestinal toxicity: including diarrhea, nausea and vomiting. In patients with breast 
cancer receiving tucatinib plus trastuzumab and capecitabine, diarrhea occurred in 81% 
of patients in the tucatinib plus trastuzumab and capecitabine arm, versus 53% of patients 
in the placebo plus trastuzumab and capecitabine arm. 
• Hepatotoxicity: Hepatotoxicity occurred in 42% of patients with breast cancer receiving 
tucatinib plus trastuzumab and capecitabine, versus 24% of patients receiving placebo 
plus trastuzumab and capecitabine, respectively. 
• Hematologic toxicity: Anemia occurred in 21% of patients receiving tucatinib plus 
trastuzumab and capecitabine, versus 13% of patients receiving placebo plus 
trastuzumab and capecitabine. 
• Embryo-fetal toxicity: In rats, oral administration of tucatinib resulted in maternal 
toxicity (body weight loss, reduced body weight gain, low food consumption) at doses 
≥90 mg/kg/day. Fetal effects included reduced number of live fetuses, decreased fetal 
weight, and fetal abnormalities (increase in skeletal variations, incomplete ossification) at 
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based on area under the curve [AUC]). In rabbits, oral administration of tucatinib resulted 
in increased resorptions, decreased percentages of live fetuses, and skeletal, visceral, and 
external malformations in fetuses at doses ≥90 mg/kg/day (1.3 times the human exposure 
at the recommended dose based on AUC). Fetal abnormalities included domed head, 
brain dilation, incomplete ossification of frontal and parietal bones, and a hole in the 
parietal bone. 
1.2.4 Trastuzumab 
Trastuzumab is a humanized anti-HER2 antibody that binds to subdomain IV of the HER2-
extracellular domain and exerts its antitumor effects by blocking HER2 cleavage, stimulating 
ADCC and inhibiting ligand-independent HER2-mediated mitogenic signaling. 
Identified safety risks as described in the regional labeling for trastuzumab are (HERCEPTIN 
2021): 
• Cardiomyopathy: Trastuzumab administration can result in subclinical and clinical 
cardiac failure. An evaluation of metastatic breast cancer clinical trials showed that 5.0% 
of patients receiving trastuzumab plus chemotherapy compared to 1.1% of patients 
receiving chemotherapy alone had LVEF value below 50% with a >10% absolute 
decrease in LVEF from pretreatment values. 
• Infusion reactions: Trastuzumab administration can result in serious and fatal infusion 
reactions. An evaluation of metastatic breast cancer clinical trials showed that 
approximately 40% of patients reported chills and fevers with their first infusion of 
trastuzumab. 
• Pulmonary toxicity: Trastuzumab administration can result in serious and fatal pulmonary 
toxicity. Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving 
trastuzumab compared with 0.3% of those receiving chemotherapy alone. 
• Exacerbation of chemotherapy-induced neutropenia: In randomized controlled clinical 
trials in the adjuvant setting, the incidence of selected National Cancer Institute Common 
Terminology Criteria (NCI-CTC) Grade 4–5 neutropenia (1.7% versus 0.8%) and of 
selected Grade 2–5 neutropenia (6.4% versus 4.3%) were increased in patients receiving 
trastuzumab and chemotherapy compared with those receiving chemotherapy alone. 
• Anemia: In randomized controlled clinical trials, the overall incidence of anemia (30% 
versus 21%), of selected NCI-CTC Grade 2–5 anemia (12.3% versus 6.7%), and of 
anemia requiring transfusions (0.1% versus no patients) were increased in patients 
receiving trastuzumab and chemotherapy compared with those receiving chemotherapy 
alone. 
• Embryo-fetal toxicity: In post-marketing reports, use of trastuzumab during pregnancy 
resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as 
pulmonary hypoplasia, skeletal abnormalities, and neonatal death. 


 
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1.2.5 Capecitabine 
Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and tissues to form 
the active moiety fluorouracil. Fluorouracil is a fluorinated pyrimidine antimetabolite that 
inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic 
acid, in turn interfering with deoxyribonucleic acid (DNA) and, to a lesser degree, ribonucleic 
acid (RNA) synthesis. 
Identified safety risks as describing in the regional labeling for capecitabine are (XELODA 
2021), (Murthy 2020): 
• Skin disorders including plantar-palmar fasciitis (hand-foot syndrome) and rash: In a 
phase 3 study, hand-foot syndrome occurred in 63% of patients receiving tucatinib plus 
trastuzumab and capecitabine, versus 53% of patients receiving placebo plus 
trastuzumab and capecitabine. In an analysis of pooled phase 3 metastatic CRC trials, 
comparing capecitabine versus 5FU/LV, hand-foot syndrome occurred in 54% (all 
grades) of patients on the capecitabine arm versus 6% (all grades) of patients on the 
5FU/LV arm. 
• Gastrointestinal toxicity: In pooled phase 3 metastatic CRC trials, comparing 
capecitabine versus 5FU/LV, diarrhea occurred in 55% (all grades) of patients on the 
capecitabine arm versus 61% (all grades) of patients on the 5FU/LV arm. 
1.3 Study Rationale 
Despite the improvements in PFS and OS achieved with the addition of new agents to first-line 
therapy for advanced or metastatic HER2pos cancers, nearly all patients will experience relapsed 
or progressive disease, and new treatment options are needed. 
T-DXd is a trastuzumab-based ADC with robust activity across multiple HER2-expressing tumor 
types, that has received US regulatory approval for second-line therapy of HER2pos gastric 
cancer. Additionally, it was recently reported that T-DXd demonstrated superior PFS compared 
to standard of care second line therapy with T-DM1 in HER2-positive breast cancer. In 
preliminary studies, T-DXd also has activity comparable to second-line standard of care 
treatment options for HER2pos CRC and HER2-expressing NSCLC. 
Tucatinib plus trastuzumab and capecitabine was recently granted US regulatory approval for 
second-line therapy of HER2pos breast cancer, and in early-phase trials studies, tucatinib plus 
trastuzumab has demonstrated antitumor activity comparable to second-line standard of care 
options in HER2pos CRC. 
The addition of immunotherapy to cytotoxic regimens could improve response rates or duration 
of response. Subjects with the tumor types eligible for this study are expected to have a low 
response rate with PD-(L)1 checkpoint inhibition, either due to relative insensitivity of the tumor 
type (HER2+ breast cancer, HER2+ colorectal cancer) or due to having already received a 
PD-(L)1 inhibitor as part of initial therapy (gastric cancer and NSCLC). However, these tumors 
are often replete with myeloid cells, which may be contributing to an immune-tolerant tumor 
microenvironment. The addition of an innate immune activator, such as a TLR8 agonist, could 
reprogram these immunosuppressive myeloid cells into immune effectors, inducing 
inflammatory cytokines, activating DCs, and recruiting T cells into the tumor. Additionally, 












 
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3. 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is a phase 1/2 open-label, multicenter, dose-escalation and expansion study designed to 
evaluate the safety, tolerability, PK, pharmacodynamics, immunogenicity, and efficacy of 
SBT6050 in combination with T-DXd (Part 1) or tucatinib and trastuzumab ± capecitabine 
(Part 2). 
The study is designed to determine the MTD, if reached, of SBT6050 when combined with 
T-DXd (Part 1) or tucatinib and trastuzumab ± capecitabine (Part 2). In dose escalation, two 
dose levels of SBT6050 are planned (0.45 mg/kg and 0.6 mg/kg). The MTD is defined as the 
dose just below the dose level with 2 or more out of 6 subjects (≥33%) experiencing DLTs. The 
DLT evaluation period is 21 days. 
Dose expansion will be initiated once the SMC has determined the SBT6050 RP2D from dose 
escalation of each respective part. The SBT6050 RP2D may be different for each of the four 
regimens. Dose expansion cohorts are designed to confirm the safety and tolerability of the 
RP2D and to evaluate efficacy and pharmacodynamic effects of SBT6050 when combined with 
T-DXd (Part 1) or tucatinib and trastuzumab ± capecitabine (Part 2). Subjects will be enrolled 
into parallel expansion cohorts based on tumor type and HER2 expression level. Throughout 
dose expansion, the Sponsor will continually monitor safety data to assess benefit versus risk for 
subjects. 
Cohorts in dose escalation and expansion may enroll subjects in parallel based on eligibility. See 
Figure 1 for the study schema. 




 
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o Cohort 1 (0.45 mg/kg SBT6050) 
o Cohort 2 (0.6 mg/kg SBT6050) 
3.1.1.2 Dose Expansion Cohorts 
• 
Part 1a (5.4 mg/kg T-DXd): 
o Cohort A: subjects with breast cancer 
o Cohort B: subjects with CRC 
o Cohort C: subjects with NSCLC 
• 
Part 1b (6.4 mg/kg T-DXd): 
o Cohort D: subjects with gastric or GEJ cancer 
3.1.2 Part 2: SBT6050 Combined With Tucatinib and Trastuzumab With or 
Without Capecitabine 
3.1.2.1 Dose Escalation Cohorts 
• 
Part 2a (tucatinib and trastuzumab + capecitabine, subjects with breast cancer or CRC): 
o Cohort 1 (0.45 mg/kg SBT6050) 
o Cohort 2 (0.6 mg/kg SBT6050) 
• 
Part 2b (tucatinib and trastuzumab without capecitabine, subjects with breast cancer or 
CRC): 
o Cohort 1 (0.45 mg/kg SBT6050) 
o Cohort 2 (0.6 mg/kg SBT6050) 
3.1.2.2 Dose Expansion Cohorts 
• 
Part 2a (tucatinib plus trastuzumab with capecitabine): 
o Cohort E: subjects with breast cancer 
• 
Part 2b (tucatinib plus trastuzumab without capecitabine): 
o Cohort F: subjects with CRC 
o Cohort G: subjects with breast cancer 
3.1.3 Dose Escalation 
Two dose levels of SBT6050 are planned (0.45 mg/kg and 0.6 mg/kg). A minimum of three and 
up to approximately six subjects will be enrolled at the starting dose of SBT6050. The DLT 
evaluation period is 21 days. The following rules will be applied: 


 
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• If 0 of 3 patients experience a DLT in the evaluation period, the next 3 subjects will be 
enrolled at the next higher dose of SBT6050. If the current dose is SBT6050 0.6 mg/kg, 
then this will be the RP2D. 
• If 1 of 3 patients experience a DLT in the evaluation period, 3 additional patients will be 
enrolled at the same dose of SBT6050. 
o If 1 of 6 subjects experience a DLT, and if the current dose is the starting dose 
level of SBT6050 (0.45 mg/kg), then the next 3 subjects will be enrolled at the 
next higher dose of SBT6050. If the current dose is SBT6050 0.6 mg/kg, then this 
will be the RP2D. 
o If ≥2 of 6 subjects experience a DLT, the MTD has been exceeded. Dose 
escalation will stop, and this dose level will be declared the maximum tolerated 
dose. If the current dose is SBT6050 0.6 mg/kg, 3 additional subjects will be 
evaluated at the prior dose level if only 3 were treated at that dose previously. 
• If 2 of 3 patients experience a DLT in the evaluation period, the MTD has been exceeded. 
Dose escalation will stop, and this dose level will be declared the maximum administered 
dose. If the current dose is SBT6050 0.6 mg/kg, 3 additional subjects will be evaluated at 
the prior dose level if only 3 were treated at that dose previously.  
• If the starting dose level of SBT6050 (0.45 mg/kg) exceeds the MTD, dose escalation 
will be stopped; the Safety Monitoring Committee (SMC) may recommend evaluation of 
a lower dose level of SBT6050 or other interventions to improve tolerability. 
The SMC will consist of Investigators and Sponsor personnel who will review DLTs and 
available safety information to determine if enrollment may then commence at the next dose 
level of SBT6050 (0.6 mg/kg). The SMC will select the RP2D level to be used for the dose 
expansion tumor-specific cohorts based on an integrated analysis of safety, PK, 
pharmacodynamic, and clinical activity data from Part 1 and Part 2 dose escalation. There will be 
an ILD Adjudication Committee, consisting of disease experts who will review available clinical 
data, radiologic images, and pathology information for suspected cases of ILD. 
3.1.3.1 Dose Limiting Toxicity 
A DLT is defined as one of the following toxicities that occur during the 21-day DLT 
observation period in Part 1 or Part 2 dose escalation and is considered by the Investigator to be 
related to the combination of SBT6050 and T-DXd or tucatinib and trastuzumab ± capecitabine. 
Part 1: SBT6050 Combined With Trastuzumab Deruxtecan 
• Any death not clearly due to the underlying disease or extraneous causes 
• Any Hy’s law case 
• Grade 4 neutropenia that lasts >7 days or with a fever >39°C (febrile neutropenia not 
meeting these criteria is not a DLT unless agreed upon by the SMC) 
• Grade 4 thrombocytopenia lasting >7 days 
• Grade ≥3 thrombocytopenia with bleeding 
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• Grade ≥3 nausea/vomiting or diarrhea lasting >72 hours with adequate antiemetic and 
other supportive care 
• Grade 3 fatigue lasting ≥1 week 
• Grade 4 fever and/or chills 
• Grade ≥3 electrolyte or serum chemistry abnormality lasting >72 hours, unless the 
subject has clinical symptoms in which case all Grade ≥3 abnormalities are considered a 
DLT regardless of duration; Note: Grade ≥3 amylase or lipase elevation not associated 
with symptoms or clinical manifestations of pancreatitis should not be considered a DLT. 
o For subjects with hepatic or bone metastases, confirmed aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) >8 × upper limit of 
normal (ULN), or AST or ALT >5 × ULN lasting for ≥14 days 
• Grade 3 hypersensitivity or allergic reaction requiring hospitalization, or Grade 4 
hypersensitivity or allergic reaction 
• Grade 3 ILD/pneumonitis confirmed by the ILD Adjudication Committee 
• Any other non-hematologic AE Grade ≥3 not clearly and incontrovertibly due to the 
underlying disease or extraneous causes 
Part 2: SBT6050 Combined With Tucatinib and Trastuzumab ± Capecitabine 
• Any death not clearly due to the underlying disease or extraneous causes 
• Any Hy’s law case 
• Grade >3 neutropenia with fever >39°C (febrile neutropenia not meeting these criteria is 
not a DLT unless agreed upon by the SMC) 
• Grade 4 thrombocytopenia lasting >7 days 
• Grade ≥3 thrombocytopenia with bleeding 
• Grade 4 anemia 
• Grade ≥3 nausea/vomiting, decreased appetite, or diarrhea lasting >72 hours with 
adequate antiemetic and other supportive care 
• Grade 3 fatigue lasting ≥1 week 
• Grade 4 fever and chills 
• Grade ≥3 electrolyte or serum chemistry abnormality lasting >72 hours (excluding ALT 
and AST elevations; see below) unless the subject has clinical symptoms in which case 
all Grade ≥3 abnormalities are considered a DLT regardless of duration. Grade ≥3 
amylase or lipase elevation not associated with symptoms or clinical manifestations of 
pancreatitis should not be considered a DLT 
• Grade 4 hepatotoxicity including ALT and AST elevations 
• Grade 3 hypersensitivity or allergic reaction requiring hospitalization, or Grade 4 
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• Any other non-hematologic AE Grade ≥3 not clearly and incontrovertibly due to the 
underlying disease or extraneous causes 
3.1.4 Replacement of Subjects 
During dose escalation, subjects who are not evaluable for the assessment of DLTs may be 
replaced to ensure the study design requirements are met. Subjects who are not evaluable for a 
DLT that discontinue due to study drug toxicity will remain in the safety population and continue 
to be followed per study requirements. 
Additional subjects may be enrolled for evaluation of alternative dosing regimens, or for further 
exploring safety, PK/pharmacodynamics, or preliminary activity used to guide the selection of 
the RP2D. 
3.1.5 End of Study 
End of study is defined as the time when the last subject has completed approximately 1 year of 
follow-up after the last dose of study treatment, has died, is lost to follow-up, or has withdrawn 
consent, whichever occurs first. In addition, the Sponsor may terminate the study at any time 
(Section 9.3.2). 


 
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4. 
STUDY POPULATION 
Subjects must meet all the enrollment criteria to be eligible for this study. 
4.1 Inclusion Criteria 
Subjects must meet all the following criteria to be enrolled in the study: 
1. Age 18 years or older  
2. For Part 1, subjects must have locally advanced (unresectable) and/or metastatic HER2-
expressing or HER2-amplified cancer as noted below and previously received the 
following therapies (unless ineligible to receive or refused to receive or therapy is 
unavailable in the region): 
• Breast cancer (dose escalation cohorts [1a] and dose expansion Cohort A): 
HER2pos (IHC 3+ or IHC 2+/HER2 amplified) 
o ≥1 prior lines of HER2-targeted therapy in the advanced setting and 
received taxane, trastuzumab, and pertuzumab in the early stage or 
advanced setting 
• CRC (KRAS, NRAS, and BRAF wild type) (dose escalation cohorts [1a] and 
dose expansion Cohort B): HER2pos (IHC 3+ or IHC 2+/HER2 amplified) or 
HER2 amplified/IHC unknown 
o ≥1 prior line of therapy and must have received chemotherapy with a 
fluoropyrimidine and oxaliplatin or irinotecan 
• NSCLC without targetable genetic alterations (eg, alterations of EGFR, 
anaplastic lymphoma kinase [ALK], ROS1, BRAF, MEK, and NTRK, etc.) 
(dose escalation cohorts [1a] and dose expansion Cohort C): HER2exp (IHC 3+ 
or IHC 2+) or HER2-amplified 
o ≥1 prior line of therapy, which must include a platinum-based 
chemotherapy, and a PD-1/PD-L1 inhibitor 
• Gastric or GEJ cancer (dose escalation cohorts [1b] and dose expansion 
Cohort D): HER2pos (IHC 3+ or IHC 2+/HER2 amplified) 
o ≥1 prior line of therapy and must have received a fluoropyrimidine, a 
platinum agent, and trastuzumab 
• Subjects in all Part 1 cohorts must not have received prior T-DXd for 
treatment of metastatic cancer 
b) For Part 2, subjects must have locally advanced (unresectable) and/or metastatic 
HER2exp or HER2-amplified cancer as noted below and previously received the following 
therapies (unless ineligible to receive or refused to receive or therapy is unavailable in the 
region): 
• Breast cancer (dose escalation cohorts [2a] and dose expansion Cohorts E and 
G): HER2pos (IHC 3+ or IHC 2+/HER2 amplified) 


 
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o ≥1 prior line of HER2-targeted therapy in the advanced setting and 
received taxane, trastuzumab, and pertuzumab in either the early stage 
or advanced setting 
• CRC (KRAS, NRAS, and BRAF wild type) (dose escalation cohorts [2b] and 
dose expansion Cohort F): HER2pos (IHC 3+ or IHC 2+/HER2 amplified) or 
HER2 amplified/IHC unknown 
o ≥1 prior line of therapy and must have received chemotherapy with 
fluoropyrimidine and oxaliplatin or irinotecan 
• Subjects in all Part 2 cohorts must not have received prior tucatinib for 
treatment of metastatic cancer 
3. Histologic confirmation of cancer and HER2 expression and/or amplification should be 
performed in a Clinical Laboratory Improvement Amendments (CLIA) (or local 
equivalent) certified laboratory: 
• Assessment of HER2 expression in subjects with breast and gastroesophageal 
cancer should follow guidelines published by the American Society of 
Clinical Oncology (ASCO), the College of American Pathologists (CAP), and 
the American Society for Clinical Pathologists (ASCP)  
• If documentation of a previous HER2 result is not available, tumor tissue 
(archival tissue or slides or fresh tissue) or a blood sample must be submitted 
to a local CLIA-certified (or local equivalent) laboratory or a Sponsor-
designated central laboratory to confirm HER2 expression and/or HER2 
amplification prior to enrollment 
4. Subjects must have a tumor lesion amenable for fresh biopsy, or be able to submit an 
adequate recent archived tumor tissue for baseline testing as follows; variations from 
tissue requirements must be discussed with the medical monitor: 
• Breast cancer and CRC:  archival biopsy tissue obtained after the last HER2-
directed therapy (excluding trastuzumab and pertuzumab), or a fresh biopsy 
• Gastric or GEJ cancer and NSCLC:  archival biopsy tissue taken within the 
past 12 months and after completion of last HER2-directed therapy, or a fresh 
biopsy 
5. Measurable disease per RECIST Version 1.1. 
6. a) For Part 1, subjects must not have history of allergic reaction, including 
hypersensitivity reactions, to the following therapies: pertuzumab, trastuzumab, or  
T-DXd 
b) For Part 2, subjects must not have history of allergic reaction, including 
hypersensitivity reactions, to the following therapies:  pertuzumab, tucatinib, 
trastuzumab, or capecitabine (for relevant cohorts) 
7. A brain magnetic resonance imaging (MRI) at baseline is required for 
• All subjects with breast cancer or NSCLC or 


 
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• Subjects with gastric or GEJ cancer or CRC who have a history of CNS 
metastases or have signs or symptoms suggestive of CNS metastasis 
8. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see 
Section 11.5) 
9. Adequate cardiac function with LVEF ≥50% 
10. Adequate hematologic function, including: 
• Absolute neutrophil count (ANC) ≥1.5 × 109/L 
• Platelet count ≥100 × 109/L (platelet transfusions are not allowed within 1 
week before screening visit) 
• Hemoglobin ≥9 g/dL (red blood cell transfusions are not allowed within 2 
weeks before screening visit) 
11. Adequate blood clotting function with prothrombin time (PT) and activated partial 
thromboplastin time/partial thromboplastin time (aPTT/PTT) <1.5 × ULN 
12. Adequate hepatic function with aspartate aminotransferase (AST) and ALT ≤2.5 × ULN 
(if liver or bone metastases are present, ≤4 × ULN) and total bilirubin ≤1.5 × ULN or <3 
× ULN in the presence of Gilbert’s syndrome 
13. Adequate renal function with estimated glomerular filtration rate (eGFR) ≥45 mL/minute 
based on Cockcroft-Gault equation 
14. Female subjects of childbearing potential and fertile male subjects with partners who are 
of childbearing potential must agree to use highly effective contraception during the 
study and for up to 7 months (for females) or 2 months (for males) after the last dose of 
SBT6050 (see Section 11.7). 
Subjects must agree not to breastfeed, starting at the time of informed consent and 
continuing through 7 months after the last dose of SBT6050 or 4 months after the last 
dose of T-DXd (Part 1) or tucatinib plus trastuzumab with or without capecitabine 
(Part 2), whichever is later. 
A female subject is considered of childbearing potential if she is anatomically and 
physiologically capable of becoming pregnant and will be or could possibly be sexually 
active with a male partner while undergoing study treatment with the possibility of 
posing harm to a fetus. 
A male subject is considered of sexual reproductive potential if he is anatomically and 
physiologically capable of causing a pregnancy in a female partner and will be or could 
possibly be sexually active with a female partner (who is or may become pregnant) while 
undergoing study treatment with the possibility of posing harm to a fetus. 
15. Subjects must have completed treatment with other systemic cancer therapy, including 
completing mAb therapy at least 4 weeks prior to first dose of study treatment, and 
completing chemotherapy or therapy with small molecules at least 2 weeks prior to first 
dose of study treatment. Local radiation therapy must have been completed at least 2 
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16. The subject or the subject’s legally acceptable representative must provide written 
informed consent. 
4.2 Exclusion Criteria 
Subjects who meet any of the following criteria will not be enrolled in the study: 
1. Prior lifetime exposure to anthracyclines exceeding: 
• Doxorubicin 360 mg/m2 
• Epirubicin 720 mg/m2 
• Mitoxantrone 120 mg/m2 
• Idarubicin 90 mg/m2 
• Liposomal doxorubicin 550 mg/m2 
2. Untreated brain metastases; subjects with treated brain metastases who are asymptomatic, 
have completed radiation therapy, and completed corticosteroid therapy at least 2 weeks 
prior to first dose of study treatment may participate 
3. Subjects requiring an equivalent of >10 mg/day of prednisone 
4. Active autoimmune disease or a documented history of autoimmune disease or syndrome 
that required systemic steroids (>10 mg/day prednisone or equivalent) or 
immunosuppressive agents within the past 2 years. Subjects are permitted to enroll if they 
have vitiligo, type 1 diabetes, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or resolved 
childhood asthma/atopy 
5. Uncontrolled or clinically significant renal, pancreas, or liver disease 
6. Subjects who are currently taking a medication which moderately induces CYP2C, a 
medication which strongly inhibits CYP2C8, or if they are taking medications that 
interact with both enzymes: CYP3A and CYP2C8 (see Section 11.8) 
7. Uncontrolled or clinically significant ILD/pneumonitis that required systemic 
corticosteroid (>10 mg prednisone per day or equivalent) treatment or suspected 
ILD/pneumonitis that cannot be ruled out by imaging at screening 
8. Positive for human immunodeficiency virus (HIV), hepatitis B (positive by surface 
antigen [HBsAg]), or hepatitis C infection (positive by ribonucleic acid polymerase chain 
reaction [HCV RNA PCR]) 
9. History of another primary invasive malignancy that has not been definitively treated and 
in remission for at least 1 year, except: 
a. Subjects with a history of prostate cancer (tumor/node/metastasis stage) of stage 
≤T2cN0M0 without biochemical recurrence or progression and who in the 
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b. Subjects who have been adequately treated for a malignancy with a low potential 
risk for recurrence (eg, cervical carcinoma in situ, non-melanomatous carcinoma 
of the skin). 
10. History of symptomatic congestive heart failure (New York Heart Association classes 
II-IV), unstable angina, myocardial infarction, serious cardiac arrhythmia, or cerebral 
vascular accident within 6 months prior to first dose of study treatment 
11. Corrected QT interval using Fridericia’s formula (QTcF) >470 msec (females) or >450 
msec (males) 
12. Other medical or psychiatric illness or organ dysfunction which, in the opinion of the 
Investigator, would either compromise the subject’s safety or interfere with the 
evaluation of the safety of the study treatment 
13. Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of 
informed consent until 7 months after final dose of SBT6050 or 4 months after final dose 
of T-DXd (Part 1) or tucatinib plus trastuzumab with or without capecitabine (Part 2), 
whichever is later 
14. Life expectancy ≤3 months, in the opinion of the Investigator 
4.3 Criteria for Discontinuation from Study Treatment and Withdrawal of 
Subjects 
Subjects are allowed to withdraw from the study at any time for any reason, without prejudice, 
and without having to justify their decision. Silverback or their designee must be notified if a 
subject is withdrawn from study treatment or from the study. The reason(s) for withdrawal must 
be documented in the subject’s medical records and electronic case report form (eCRF). 
4.3.1 Discontinuation of Study Treatment 
Subjects may be discontinued from study treatment for any of the following reasons: 
• 
Completed 2 years of treatment 
• 
Progression of disease 
• 
Development of unacceptable toxicity  
• 
Confirmed pregnancy 
• 
Death 
• 
Withdrawal of consent 
• 
Subject decision 
• 
Lost to follow-up 
• 
Study termination by Sponsor 
• 
Other reason (eg, Investigator decision) 


 
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Subjects who discontinue one of the study drugs due to toxicity considered related to that drug 
may continue therapy with the other agent(s), respectively, for up to 2 years at the discretion of 
the Investigator after discussion with the medical monitor. 
Subjects who present equivocal findings of progression (eg, very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions) or suspected pseudoprogression 
(temporary increase in size of tumor lesions due to inflammation), may be allowed to continue 
the study treatment with approval of the medical monitor and if, in the opinion of the 
Investigator, the subject is deemed clinically stable. Subjects with progressive disease based on 
small or equivocal lesions or lesions amenable to local therapy (eg, radiation therapy) may be 
allowed to continue the study treatment with approval of the medical monitor and if, in the 
opinion of the Investigator, the subject is deemed clinically stable. If, at the next scheduled 
assessment progression is confirmed, the date of progression should be the date when 
progression was initially suspected. 
Subjects who discontinue from study treatment prior to radiographic evidence of progressive 
disease will continue to be contacted for disease progression (eg, tumor response 
assessments/scans) until radiographic evidence of disease progression, treatment with another 
anticancer therapy, or withdrawal of consent. Long-term follow-up will continue for all subjects 
until death, withdrawal of consent, lost to follow-up, study termination by Sponsor, end of study, 
or other reason. 
4.3.2 Discontinuation From the Study 
Subjects may be discontinued from the study for any of the following reasons: 
• 
Death 
• 
Withdrawal of consent 
• 
Lost to follow-up 
• 
Study termination by Sponsor  
• 
End of study 
• 
Other 
 


 
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5. 
STUDY TREATMENTS 
5.1 Treatments Administered 
The planned dose levels of SBT6050 in this study are based on the initial results from the 
ongoing dose-escalation phase 1/1b clinical study Protocol SBT6050-101 (NCT04460456).  
T-DXd dose levels are based on the approved doses for HER2pos breast cancer and gastric or GEJ 
cancer (ENHERTU 2021) and on clinical trial data for NSCLC and CRC. Tucatinib, 
trastuzumab, and capecitabine dose levels are based on approved doses for HER2pos breast 
cancer (TUKYSA 2020) and clinical trial data for CRC. See the national prescribing information 
(PI) for details. 
Biosimilar or therapeutic equivalents of the drugs of the study drug (eg, trastuzumab) are 
acceptable. 
In Part 1, the following treatments will be administered (see Figure 1): 
• Subjects with breast cancer, CRC, and NSCLC: 
1. SBT6050 (0.3–0.6 mg/kg or RP2D) will be administered by SC injection 
on Day 1 of each 21-day cycle 
2. T-DXd (5.4 mg/kg) will be administered by IV infusion on Day 1 of each 
21-day cycle 
• Subjects with gastric/GEJ cancer: 
1. SBT6050 (0.3–0.6 mg/kg or RP2D) will be administered by SC injection 
on Day 1 of each 21-day cycle 
2. T-DXd (6.4 mg/kg) will be administered by IV infusion on Day 1 of each 
21-day cycle 
In Part 2, the following treatments will be administered to subjects with breast cancer and CRC 
(see Figure 1): 
1. SBT6050 (0.3–0.6 mg/kg or RP2D) will be administered by SC injection on Day 
1 of each 21-day cycle 
2. Trastuzumab (8 mg/kg loading dose; 6 mg/kg subsequent cycles) will be 
administered by IV infusion on Day 1 of each 21-day cycle 
3. Tucatinib (300 mg PO twice daily [BID]) starting on Day 1 of the first cycle and 
for the duration of study treatment 
4. If applicable based on cohort enrollment: Capecitabine (1000 mg/m2 PO BID) on 
Days 1–14 of each cycle 
5.2 Investigational Product: SBT6050 
Detailed information describing the preparation, administration, and storage of SBT6050 is 
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5.2.4 Packaging and Labeling of SBT6050 
Each vial of SBT6050 will be labeled in compliance with applicable regulatory requirements. 
Refer to the Pharmacy Manual for information regarding packaging and labeling of SBT6050. 
5.2.5 Preparation of SBT6050 
Detailed drug preparation instructions for SBT6050 are provided in the Pharmacy Manual. 
5.3 Part 1: SBT6050 Combined With Trastuzumab Deruxtecan 
For subjects with breast cancer, CRC, or NSCLC, T-DXd will be administered at 5.4 mg/kg via 
IV infusion over 90 minutes (Cycle 1) or over 30 minutes (subsequent cycles) on Day 1 of every 
21-day cycle. 
For subjects with gastric/GEJ cancer, T-DXd will be administered at 6.4 mg/kg via IV infusion 
over 90 minutes (Cycle 1) or over 30 minutes (subsequent cycles) on Day 1 of every 21-day 
cycle. 
T-DXd infusion should begin at least 15 minutes after the injection of SBT6050. Infusion rates 
may be slowed if the subject develops an infusion-related symptom (see Section 5.6.1).  
T-DXd should be prepared, administered, and stored, per instructions in the currently approved 
regional labeling and under the direction of the Investigator (eg, ENHERTU® USPI). 
5.4 Part 2: SBT6050 Combined With Tucatinib and Trastuzumab ± Capecitabine 
Part 2 of the study includes tucatinib and trastuzumab with capecitabine (Part 2a) or without 
capecitabine (Part 2b). Tucatinib, trastuzumab and capecitabine will be supplied as described in 
the Pharmacy Manual. 
5.4.1 Tucatinib 
Tucatinib 300 mg PO BID will be taken by all Part 2 subjects starting on Cycle 1 Day 1 and for 
the duration of study treatment. Tucatinib should be taken after administration of SBT6050 and 
trastuzumab in the clinic on Cycle 1 Day 1. On Day 1 of each subsequent cycle, study staff 
should review tucatinib compliance from previous cycle. 
Tucatinib should be prepared, administered, and stored per instructions in the currently approved 
regional labeling and under the direction of the Investigator (eg, TUKYSA® USPI). Per the 
labeling, tucatinib can be taken with or without food. 
5.4.2 Trastuzumab 
Trastuzumab 8mg/kg will be administered to all Part 2 subjects on Cycle1 Day 1 by IV infusion 
over 90 minutes. 
Trastuzumab 6 mg/kg will be administered to all Part 2 subjects on Cycle 2 Day 1 and Day 1 of 
all subsequent cycles, by IV infusion over 30–90 minutes. 


 
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Trastuzumab infusion should begin at least 15 minutes after the injection of SBT6050. Infusion 
rates may be slowed if the subject develops an infusion-related symptom (see Section 5.6.1).  
Trastuzumab should be stored, prepared, and administered per instructions in the currently 
approved regional labeling and under the direction of the Investigator (eg, HERCEPTIN® 
USPI). 
5.4.3 Capecitabine 
Capecitabine 1000 mg/m2 PO BID will be taken by subjects in Part 2a of dose escalation and 
Cohort E of dose expansion, on Day 1–14 of each cycle. Capecitabine should be taken after 
administration of SBT6050 and trastuzumab in the clinic on Cycle 1 Day 1. On Day 1 of each 
subsequent cycle, study staff should review capecitabine compliance from previous cycle. 
The dose administered may not exactly match the calculated dose because capecitabine is an oral 
drug available in fixed doses. Local institutional practices should be followed to determine 
rounding of capecitabine doses for administration. Documentation of both the calculated and 
administered dose should be captured. 
Capecitabine should be prepared, administered, and stored per instructions in the currently 
approved regional labeling and under the direction of the Investigator (eg, XELODA® USPI). 
Per its labeling, it is recommended that capecitabine be taken within 30 minutes of a meal. 
5.5 Concomitant Medications 
5.5.1 Required Premedication and Postmedication 
All subjects should receive the following prophylactic medications with each subsequent dose of 
SBT6050 after the first dose, if needed. Contraindications or other exceptions for individual 
subjects, including subjects who discontinue one of the study drugs, should be discussed with the 
medical monitor. 
In Part 1, subjects are required to receive 
• Ondansetron (or equivalent) 16 mg IV once at least 30 minutes prior to the dose of 
SBT6050 and then 8 mg PO every 8 hours as needed (PRN) for nausea and/or vomiting 
starting 8 hours after the prior dose of ondansetron 
• 
Dexamethasone (or equivalent) 8 mg PO every day for 3 days, beginning the day prior to 
Day 1 of each cycle, on Day 1 of each cycle at least 30-60 minutes prior to SBT6050 
dosing, and ending on Day 2 of each cycle 
In Part 2, subjects are required to receive 
• 
Dexamethasone (or equivalent) 8 mg PO on Day 1 of each cycle at least 30-60 minutes 
prior to SBT6050 dosing 
• 
Ondansetron (or equivalent) 8 mg PO every 8 hours PRN for nausea and/or vomiting 
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• Acetaminophen (or equivalent) 650–1000 mg PO within approximately 1 hour prior to 
the dose, and then every 4-6 hours for 2 days post dose (not to exceed 3250 mg in 
24 hours) and then as needed for pyrexia or pain 
• An antihistamine, given within approximately 1 hour prior to each dose and then as 
needed, such as:  
o diphenhydramine 25–50 mg PO or IV 
o cetirizine 10 mg PO or IV, or 
o loratadine 10 mg PO 
• Intravenous fluid supplementation as appropriate prior to each dose, and the day after 
each dose, per the Investigator’s assessment, to prevent dehydration and hypotension 
• Topical high-potency corticosteroid applied to the area 5-10 cm around the planned 
injection site, at least one hour and, optimally, up to 24 hours prior to the injection, such 
as: 
o clobetasol proprionate 0.05% cream 
o halobetasol proprionate 0.05% cream 
o betamethasone dipropionate 0.05% cream, or an equivalent 
5.5.2 Recommended Supportive Medications 
Supportive medications that may be useful for some subjects include the following, which may 
be given as needed, or as pre-medication based on the treating physician’s medical judgement: 
• Anti-nausea medications including 5-HT3 inhibitors such as  
o ondansetron 8 mg PO twice daily as needed for nausea 
o palonosetron 0.25 mg IV or 0.5 mg PO as a single dose, as needed for nausea 
• Non-steroidal anti-inflammatory medication such as ibuprofen 400 mg PO every 4-6 
hours or naproxen sodium 220 mg PO every 8-12 hours for pyrexia or pain 
• Meperidine 25-50 mg IV as a single injection, as needed to treat shaking chills (rigors) 
• Intravenous fluid, per institutional standards, to prevent dehydration 
• Systemic corticosteroid as needed to treat ≥Grade 3 hypotension (not responding to IV 
fluid infusion), ≥Grade 3 hypoxia, or ≥Grade 2 CRS, such as 
o methylprednisolone 1 mg/kg IV or equivalent, given as a single dose  
o dexamethasone 8-12 mg IV/PO given as a single dose 
5.5.3 Allowed Concomitant Therapy 
Corticosteroids and other immunosuppressive therapies may be used to treat acute AEs; 
however, given that the mechanism of action of corticosteroids may interfere with SBT6050 
activity, their use should be minimized in the context of best supportive care and carefully 
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Non-systemic corticosteroids, including inhaled, topical, intranasal, intra-articular, and 
ophthalmic steroids are permitted. 
All other concomitant medications, blood products, other non-drug therapies (eg, procedures), 
and radiotherapy administered will be recorded if new or ongoing from informed consent 
through the safety reporting period. 
Standard supportive care medications will be permitted, including use of growth factors or blood 
product transfusions as required to treat AEs. Growth factors (eg, colony-stimulating factors or 
erythropoietin) should not be used prophylactically. 
Subjects who are on a stable dose of luteinizing hormone-releasing hormone agonists for 
maintenance of postmenopausal endocrine state may continue therapy. 
Supportive therapies for bone metastases, including bisphosphonates and RANK-ligand 
inhibitors (eg, denosumab) are allowed; however, initiation of these therapies during the first 
cycle of study treatment should be avoided to prevent confounding the assessment of safety. 
Routine vaccination with inactivated, subunit, recombinant, polysaccharide, and conjugate 
vaccines are permitted but should not be administered within 5 days before or after SBT6050 and 
should be avoided during the first cycle of study treatment. Live attenuated viral vaccines such as 
the intranasal influenza vaccine are not permitted while on study drug. 
Required premedication is described in Section 5.5.1. Other medication that is not specifically 
excluded will be allowed during the study to manage any subject clinical condition. 
5.5.4 Prohibited Concomitant Therapy 
Subjects requiring chronic immunosuppressive therapy at baseline (eg, requiring equivalent of 
>10 mg/day of prednisone) are not eligible for the study. Temporary immunosuppressive therapy 
(eg, corticosteroid premedication for imaging studies) should be completed at least 1 week prior 
to first dose of study treatment. 
Anticancer agents (except study drugs), including chemotherapy, endocrine therapy (except as 
noted in Section 5.5.3), immunotherapy, and experimental therapies are prohibited. Palliative 
radiation therapy is generally not allowed but may be considered in select cases after discussion 
with the medical monitor. 
In Part 2, subjects must avoid concomitant use of strong CYP3A inducers or moderate CYP2C 
inducers, strong CYP2C8 inhibitors, and CYP3A substrates; the Investigator should also 
consider reducing the dose of P-glycoprotein (P-gp) substrate drug (see Section 11.8). 
Additionally, subjects in Part 2 must avoid using tanning lights and booths and should cover 
their skin and use sunscreen when in the sun (or exposed to UV radiation) as much as possible. 
5.6 Dose Modifications 
5.6.1 Dose Modifications for SBT6050 and T-DXd 
In both Part 1 and Part 2, subjects who experience DLT during the DLT assessment period 
should not receive SBT6050 or T-DXd unless the toxicity resolves to Grade 1 or baseline, and 
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defined by the medical monitor in discussion with the site Investigator in the context of the type 
of AE observed. In the event a subject is unable to tolerate their dose level, additional treatment 
cycles (Cycle 2 or later) may be administered at a lower dose level upon approval by the medical 
monitor. 
Slow or interrupt the T-DXd infusion rate if the subject develops infusion-related symptoms. 
Permanently discontinue T-DXd in case of severe infusion-related reactions. 
LVEF should be assessed prior to initiation of SBT6050 and at regular intervals (ie, every 12 
weeks) during treatment. Management of adverse reactions may require temporary interruption, 
dose reduction, or treatment discontinuation of T-DXd and SBT6050 as described in Table 1, 
Table 2, and Table 3. 
Table 2: 
T-DXd dose reduction schedule 
Dose reduction schedule 
Dose level 
Dose level 
Recommended starting dose 
5.4 mg/kg 
6.4 mg/kg 
First dose reduction (DL-1) 
4.4 mg/kg 
5.4 mg/kg 
Second dose reduction (DL-2) 
3.2 mg/kg 
4.4 mg/kg 
Requirement for further dose reduction 
Discontinue treatment 
Discontinue treatment 
 
 


 
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Table 3: 
Recommended dose modifications for SBT6050 and T-DXd 
Adverse Reaction 
Severity 
Action to be taken for SBT6050 
Action to be taken for T-DXd 
Interstitial lung 
disease/pneumonitis 
Grade 1 
(asymptomatic) 
Interrupt SBT6050 until resolved to Grade 
0, then: 
Interrupt T-DXd until resolved to Grade 0, 
then: 
• If resolved in 28 days or less from date of onset, maintain dose 
• If resolved in greater than 28 days 
from date of onset, maintain SBT6050 
dose (see Table 1) 
• If resolved in greater than 28 days from 
date of onset, reduce T-DXd dose 1 level 
(see Table 2) 
• Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected 
≥Grade 2 
(symptomatic)  
• Permanently discontinue SBT6050 
• Permanently discontinue T-DXd 
• Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected 
Neutropenia 
Grade 3 
• Interrupt study treatment until resolved to ≤ Grade 2, then maintain dose 
Grade 4 
• Interrupt study treatment until resolved to ≤ Grade 2 
• Maintain dose for SBT6050 (see  
Table 1) 
• Reduce T-DXd dose 1 level (see  
Table 2) 
Thrombocytopenia 
Grade 3 
• Interrupt study treatment until resolved to ≤ Grade 1, then maintain dose 
Grade 4 
• Interrupt study treatment until resolved to ≤ Grade 1 
• Maintain SBT6050 dose (see Table 1) 
• Reduce T-DXd dose 1 level (see  
Table 2) 
LVEF 
>45% AND absolute decrease from 
baseline is 10%–20%  
• Continue treatment 


 
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Adverse Reaction 
Severity 
Action to be taken for SBT6050 
Action to be taken for T-DXd 
40%–45% 
AND absolute 
decrease from baseline 
is <10% 
• Continue treatment 
• Repeat LVEF assessment in 3 weeks 
AND absolute 
decrease from baseline 
is 10%–20% 
• Interrupt treatment 
• Repeat LVEF assessment in 3 weeks 
• If LVEF has not recovered to within 10% from baseline, permanently discontinue 
treatment 
• If LVEF recovers to within 10% from baseline, resume treatment at the same dose 
level 
<40% or absolute decrease from 
baseline is >20% 
• Interrupt treatment 
• Repeat LVEF assessment in 3 weeks 
• If LVEF of <40% or absolute decrease of baseline of >20% is confirmed, permanently 
discontinue treatment 
Symptomatic congestive heart failure 
• Permanently discontinue treatment 
Other adverse events 
Grade 3 
• Hold SBT6050 until recovery to 
≤ Grade 1, then resume SBT6050 at 
the same or reduced dose level if 
related to SBT6050 as per the 
Investigator.  
Hold T-DXd until recovery to ≤ Grade 1, 
then resume SBT6050 at the same or 
reduced dose level if related to T-DXd 
as per the Investigator. 
 
Grade 4 
Permanently discontinue SBT6050. 
Permanently discontinue T-DXd. 
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v.4.03). 
 


 
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Refer to the currently approved regional labeling (eg, ENHERTU® USPI) for T-DXd-related 
dose modifications. 
Subsequent doses of SBT6050 should be held for ≥Grade 3 AEs or toxicities until resolved to 
Grade 1 or baseline. Doses of study drugs may be held for toxicity for up 21 days; delays of 
>21 days must be discussed with the medical monitor. 
5.6.2 Dose Modifications for Tucatinib plus Trastuzumab ± Capecitabine 
Management of adverse reactions may require temporary interruption, dose reduction, or 
treatment discontinuation of SBT6050, tucatinib-, trastuzumab-, and capecitabine (if applicable)-
related dose modifications as described in Table 1, Table 4, and Table 5. 
Table 4: 
Tucatinib dose reduction schedule 
Dose reduction schedule 
Tucatinib dosing 
Recommended starting dose 
300 mg orally twice daily 
First dose reduction (DL-1) 
250 mg orally twice daily 
Second dose reduction (DL-2) 
200 mg orally twice daily 
Third dose reduction (DL-3) 
150 mg orally twice daily 
 


 
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Table 5: 
Recommended dose modifications for SBT6050, tucatinib, trastuzumab, and capecitabine 
Adverse 
Reaction 
Severity 
Action to be Taken With 
SBT6050 
Action to be Taken With 
Tucatinib  
Action to be Taken With 
Trastuzumab 
Action to be Taken With 
Capecitabine 
LVEF 
>45% AND absolute 
decrease from baseline 
is 10%–20% 
• Continue treatment 
40%–
45% 
AND absolute 
decrease from 
baseline is 
<10% 
• Continue treatment 
• Repeat LVEF assessment in 3 weeks 
AND absolute 
decrease from 
baseline is 
10%–20% 
• Interrupt treatment 
• Repeat LVEF assessment in 3 weeks 
• If LVEF has not recovered to within 10% from baseline, permanently discontinue treatment 
• If LVEF recovers to within 10% from baseline, resume treatment at the same dose level 
<40% or absolute 
decrease from baseline 
is >20% 
• Interrupt treatment 
• Repeat LVEF assessment in 3 weeks 
• If LVEF of <40% or absolute decrease of baseline of >20% is confirmed, permanently discontinue treatment 
Symptomatic 
congestive heart failure 
• Permanently discontinue treatment 
Diarrhea 
Grade 3 (without anti-
diarrheal treatment) 
• Initiate or intensify appropriate medical therapy. Hold treatment until recovery to ≤Grade 1, then resume 
treatment at the same dose level 
Grade 3 (with anti-
diarrheal treatment) 
• Initiate or intensify 
appropriate medical 
therapy. Hold 
SBT6050 until 
recovery to ≤ Grade 
1, then resume 
SBT6050 at the same 
dose level 
• Initiate or intensify 
appropriate medical 
therapy. Hold 
tucatinib until 
recovery to ≤ Grade 
1, then resume 
tucatinib at the next 
lower dose level 
• Initiate or intensify appropriate medical therapy. 
Hold treatment until recovery to ≤ Grade 1, then 
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Adverse 
Reaction 
Severity 
Action to be Taken With 
SBT6050 
Action to be Taken With 
Tucatinib  
Action to be Taken With 
Trastuzumab 
Action to be Taken With 
Capecitabine 
Grade 4 
• Permanently discontinue treatment 
Hepatotoxicity 
Grade 2 bilirubin 
• Hold treatment until recovery to ≤ Grade 1, then resume treatment at the same dose level.  
Grade 3 ALT or AST, 
OR Grade 3 bilirubin 
• Hold SBT6050 until 
recovery to ≤ Grade 
1, then resume 
SBT6050 at the same 
dose level.  
• Hold tucatinib until 
recovery to ≤ Grade 
1, then resume 
tucatinib at the next 
lower dose level.  
• Hold treatment until recovery to ≤ Grade 1, then 
resume treatment at the same dose level. 
Grade 4 ALT or AST 
OR Grade 4 bilirubin 
• Hold SBT6050 until 
recovery to ≤ Grade 
1, then resume 
SBT6050 at the same 
or reduced dose level 
if related to SBT 
6050 as per 
Investigator 
• Permanently 
discontinue tucatinib, 
regardless of 
relationship. 
• Hold trastuzumab until 
recovery to ≤ Grade 1, 
then resume treatment 
at the same dose level. 
• Hold capecitabine 
until recovery to 
≤ Grade 1, then 
resume capecitabine at 
the same or reduced 
dose level as per 
Investigator 
ALT or AST >3xULN 
AND bilirubin 
>2xULN 
• Permanently discontinue treatment. 
Other adverse 
events 
Grade 3 
• Hold SBT6050 until 
recovery to ≤ Grade 
1, then resume 
SBT6050 at the same 
or reduced dose level 
if related to SBT 
6050 as per 
Investigator.  
• Hold tucatinib until 
recovery to ≤ Grade 
1, then resume 
tucatinib at the next 
lower dose level if 
related to tucatinib as 
per Investigator.  
• Hold trastuzumab until 
recovery to ≤ Grade 1, 
then resume 
trastuzumab at same 
or reduced dose level 
if related to 
trastuzumab as per 
Investigator.  
• Hold capecitabine 
until recovery to 
≤ Grade 1, then 
resume capecitabine at 
reduced dose level if 
related to capecitabine 
as per Investigator  
Grade 4 
• Permanently discontinue treatment.  
ULN=upper limit of normal 
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v.4.03) 


 
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Refer to the currently approved regional labeling (eg, TUKYSA® USPI) for additional tucatinib-
, trastuzumab-, and capecitabine (if applicable)-related dose modifications. 
Subsequent doses of SBT6050 should be held for ≥ Grade 3 AEs or toxicities until resolved to 
Grade 1 or baseline. Doses of study drugs may be held for toxicity for up to 21 days; delays of 
>21 days must be discussed with the medical monitor. 
5.7 Management of Overdose 
Overdose is defined as the administration of a quantity of study drug given per administration or 
cumulatively that is above the maximum dose according to the protocol. Overdoses will be 
collected as part of investigational product dosing information and/or as a protocol violation, as 
required. Any AE associated with an overdose should be recorded on the AE eCRF with the 
diagnosis of the AE. 
5.8 Treatment Compliance 
Data regarding the administration and dose of T-DXd and trastuzumab, as well as the number of 
tablets of tucatinib and capecitabine taken will also be collected by the site after each cycle. Dose 
modifications and interruptions of any study drug will be documented in the source documents 
and the electronic case report form (eCRF). 
5.9 Study Drug Accountability 
SBT6050 used during the course of the study should be handled according to the Pharmacy 
Manual. Accountability for SBT6050 at the study site is the responsibility of the Investigator. 
The Investigator will ensure that SBT6050 is used only in accordance with this protocol. Where 
allowed, the Investigator may choose to assign drug accountability responsibilities to a licensed 
pharmacist or other appropriate individual. SBT6050 will be tracked and documented from the 
time of receipt at the site, through subject dosing, until the Sponsor approves of the final return 
or destruction. 
The Investigator or delegate will maintain accurate drug accountability records indicating the 
drug’s delivery date to the site, inventory at the site, use by each subject, and return to the 
Sponsor or its designee (or disposal of the drug, if approved by the Sponsor). These records will 
adequately document that the subjects were provided the doses as specified in the protocol and 
should reconcile all study drug received from the Sponsor. The Sponsor or its designee will 
review drug accountability at the site on an ongoing basis during site visits. 
Sites will also be required to provide accountability for administration of T-DXd, trastuzumab, 
tucatinib and capecitabine for entry into the eCRF. 
All unused and used study drug should be handled according to the Sponsor’s instructions in the 
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o Coagulation panel, which will include PT/international normalized ratio (INR) 
and PTT (or, depending on institutional standard, aPTT). 
o Genomic DNA. If this sample is not collected during Screening, it can be 
obtained during any future clinical visit. 
o Peripheral blood for PK and biomarker analyses (see Section 6.4.2) 
o Hematology and chemistry panels 
• 
Baseline tumor assessment by computed tomography (CT), positron emission 
tomography (PET)/CT (if diagnostic-quality CT scan included) or MRI of chest, 
abdomen, and pelvis, as well as other appropriate imaging of known sites of disease (eg, 
bone scan). 
• 
A brain MRI is required at baseline for all subjects with breast cancer or NSCLC, or 
subjects with gastric/GEJ cancer or CRC who have a history of CNS metastases or have 
signs or symptoms suggestive of CNS metastasis. 
• 
Physical examination (including height and weight) 
• 
Pregnancy test for subjects of childbearing potential 
• 
Vital sign measurements, which include systolic and diastolic blood pressure, heart rate, 
respiratory rate, and temperature. Assessments should be conducted while the subject is 
either seated or supine. 
• 
12-lead electrocardiogram (ECG) 
• 
Echocardiogram (ECHO)/multi-gated acquisition (MUGA) scan 
• 
ECOG performance status 
• 
Saturated oxygen (SpO2) levels by pulse oximetry 
• 
Collection of prior and concomitant medications and AEs 
6.2 Efficacy Measurements 
Tumor response will be evaluated as specified in the Schedule of Assessments (Section 11.1 and 
Section 11.2) using radiographic evidence of progressive disease according to RECIST Version 
1.1 using unidimensional measurement such as CT, PET/CT scan (if diagnostic-quality CT scan 
included), or MRI. At a minimum, scans must include chest, abdomen, and pelvis, as well as 
appropriate imaging of any other known sites of disease (eg, bone scan or MRI in case of 
previously documented brain metastases). 
Subjects who experience an objective response (ie, tumor reduction) should have a confirmatory 
assessment performed approximately 4 weeks after the initial response. 
6.3 Pharmacokinetic Measurements 
Blood samples for measurements of SBT6050, tAb, and free payload (S-00193) will be collected 
at time points specified in the Schedule of Assessments (Section 11.1 and Section 11.2). Samples 
will be collected, processed, and stored based on procedures presented in the Laboratory Manual. 








 
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6.6.6 Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status scales are used to assess how a subject’s disease is progressing 
and assess how the disease affects the activity of daily living of the subject. The ECOG 
performance status scales are available in Section 11.5. 
6.6.7 Oxygen Saturation 
Oxygen saturation (SpO2) will be obtained to assess the subjects’ amount of oxygen in blood 
hemoglobin and to identify hypoxemia and/or hypoxia. 
6.6.8 Clinical Laboratory Tests 
Blood and urine samples will be collected and processed according to the instructions from the 
local laboratories. Samples will be reported by the local laboratories against their normal 
reference ranges. 
Hematology analytes will include erythrocytes, hemoglobin, hematocrit, platelets, leucocytes and 
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes, as 
percentages and absolute values, if available). Analyses for complete blood count, white blood 
cell differential, and reticulocyte count will also be performed.  
Clinical chemistry analytes will include: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, calcium, phosphate, magnesium, creatinine, total protein, albumin, glucose, total and 
direct bilirubin, amylase, alkaline phosphatase (ALP), ALT, AST, lactate dehydrogenase, 
γ-glutamyl transferase, lipase, triglycerides, thyroid-stimulating hormone, and troponin. 
Creatinine clearance will be calculated using the Cockcroft-Gault formula.  
Cholesterol (total, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol) is 
only required at baseline. 
 
6.7 Long-term Follow-up (Every 3 Months After 30-day Follow-up Visit) 
Approximately every 3 months after the 30-day follow-up visit, subjects will be followed for 
survival, disease status, and subsequent anticancer therapies until death, withdrawal of consent, 
lost to follow-up, study termination by Sponsor, or 1 year after the last dose of study treatment 
has been administered to the last subject. Reasonable efforts should be made to follow subjects 
who are lost to follow-up either by direct contact or collecting public records (eg, death 
certificates) as allowed by local and/or regional laws. 
6.8 End of Study/End of Follow-up 
The date the subject met criteria for study discontinuation and the reason for study 
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6.9 Adverse Events 
Monitoring of AEs will be conducted throughout the study. Adverse events will be recorded in 
the eCRF from time of signing informed consent through 30 days after the last dose of study 
drug (SBT6050, T-DXd, tucatinib, trastuzumab, or capecitabine). 
All SAEs will be recorded in the eCRF from the initiation of study drug through 30 days after the 
last dose of study drug (SBT6050, T-DXd, tucatinib, trastuzumab, or capecitabine). If an SAE 
occurs between the time of signing informed consent but prior to the initiation of study drug, it 
should only be recorded in the eCRF if caused by a protocol-mandated intervention. 
In addition, SAEs that are assessed as related to study treatment that occur >30 days after the last 
dose of study treatment are also to be reported. All AEs should be monitored until they are 
resolved or are clearly determined to be due to a subject’s stable or chronic condition or 
intercurrent illness(es). 
6.9.1 Definitions 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience)  
can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), clinically 
significant ECG change, symptom, complications that occur as a result of protocol-mandated 
procedures, or disease temporally associated with the use of a drug, without any judgment about 
causality. An AE can arise from any use of the drug (eg, off label use, use in combination with 
another drug) and from any route of administration, formulation, or dose, including an overdose. 
Adverse Event Severity 
Severity of all AEs, including clinically significant treatment-emergent laboratory abnormalities, 
will be graded according to the NCI CTCAE Version 5.0 (see Section 11.3). Adverse events not 
listed by the CTCAE will be graded as follows: 
• Mild: The event is noticeable to the subject but does not interfere with routine activity. 
• Moderate: The event interferes with routine activity but responds to symptomatic therapy 
or rest. 
• Severe: The event significantly limits the subject’s ability to perform routine activities 
despite symptomatic therapy. 
• Life-threatening: An event in which the subject was at risk of death at the time of the 
event. 
• Fatal: An event that results in the death of the subject. 
Relationship of the Adverse Event to Study Treatment 
Relationship to study drug administration will be determined by the Investigator according to the 
criteria listed below. Where study treatment is a combination therapy, assessment of causality 
should be to each individual product administered as part of the regimen as follows: 


 
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• Not Related: Exposure to the study treatment did not occur, or the occurrence of the AE 
is not reasonably related in time, or the AE is considered unlikely to be related to the 
study treatment. 
• Related: A clinical event occurs in a plausible time relationship to treatment 
administration, and which concurrent disease or other drugs or chemicals cannot explain. 
The response to withdrawal of the treatment should be clinically plausible. 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to the study drug. The following guidance should be taken into 
consideration: 
• Temporal relationship of event onset to the initiation of study drug. 
• Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or reintroduction of study drug (where applicable). 
• Known association of the event with the study drug or with similar treatments. 
• Known association of the event with the disease under study. 
• Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event 
• Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event. 
Suspected Adverse Reaction 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of expedited safety reporting, ‘reasonable possibility’ means 
there is evidence to suggest a causal relationship between the drug and the AE. 
Unexpected Adverse Event  
An unexpected AE is one for which the nature or severity of the event is not consistent with the 
applicable product reference safety information (eg, the Investigator’s Brochure). 
Serious Adverse Event 
An AE or suspected adverse reaction is considered serious if, in the opinion of either the 
Investigator or Sponsor, it results in any of the following: 
• 
Death (ie, the AE actually causes or leads to death). 
• 
Life-threatening. Life-threatening means that the subject was at immediate risk of death 
from the reaction as it occurred (ie, it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form). 
• 
In-patient hospitalization or prolongation of existing hospitalization. Hospitalizations 
solely for the purpose of receiving supportive care treatment, observation following 
dosing, or hospitalization admissions and/or surgical operations scheduled to occur 
during the study period, but planned prior to study entry are not considered AEs if the 
illness or disease existed before the subject was enrolled in the study, provided that it did 


 
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not deteriorate in an unexpected manner during the study (eg, surgery performed earlier 
than planned). 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug. 
• 
Important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment by the Investigator or the Sponsor, it may 
jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in the definitions for SAEs. 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 in-patient hospitalization, or the 
development of drug dependency or drug abuse. 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(rated as mild, moderate, or severe, or according to NCI CTCAE criteria); the event itself may be 
of relatively minor medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on the eCRF. 
6.9.2 Procedures for Eliciting and Recording Adverse Events 
Each subject must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of nonleading questions (eg, “How are you feeling?”) and from 
signs and symptoms detected during each examination, observations of study personnel, and 
spontaneous reports from subjects. 
Eliciting Adverse Events 
All AEs (serious and nonserious) spontaneously reported by the subject and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded on the appropriate page of the eCRF.  
Any clinically relevant deterioration in laboratory assessments (see Section 6.9.2) for capturing 
abnormal laboratory findings as AEs) or other clinical findings is considered an AE and must be 
recorded on the appropriate pages of the eCRF. When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event except for AEs 
associated with study treatment administration (see Section 6.9.4). 
Recording Adverse Events 
All AEs, whether serious or not, will be described in the source documents and on the AE page 
of the eCRF. All new events that occur after signing the informed consent, including those that 
worsen in severity or frequency relative to baseline, must be recorded. Adverse events that are 
ongoing at the time of treatment discontinuation should be followed through the 30-day follow 
up visit. Serious adverse events felt by the Investigator to be related to study treatment, however, 
must be reported any time the Investigator becomes aware of such an event, even if this 
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Information to be reported in the description of each AE includes: 
• A medical diagnosis of the event (if a medical diagnosis cannot be determined, a 
description of each sign or symptom characterizing the event should be recorded).  
• The date and time of onset of the event.  
• The date and time of resolution of the event. 
• Whether the event is serious or not. 
• Severity of the event (see below for definitions). 
• Relationship of the event to study treatment (see below for definitions). 
• Action taken with study treatment: dose not changed; dose reduced; drug interrupted; 
drug withdrawn; not applicable (eg, AE occurred prior to the first dose of study 
medication; unknown; information in the medical record should include drug treatment 
and non-drug treatment and diagnostic procedures performed related to the event, if 
applicable. 
• Outcome: not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; recovering/resolving; died; unknown. 
• The subject was discontinued from study treatment due to the AE 
• Treatment was administered 
• The event met the criteria of a DLT 
Investigators should use correct medical terminology/concepts when recording AEs on the AE 
eCRF and avoid colloquialisms and abbreviations. Only 1 AE term should be recorded in each 
event field on the AE eCRF. 
Recording Serious Adverse Events 
All SAEs and follow-up to previously reported SAEs that occur during the study must be 
promptly reported by the Investigator. Deaths and AEs assessed as life-threatening are to be 
reported immediately and SAEs that meet other criteria are to be reported within 24 hours from 
the time when the Investigator becomes aware of the SAE. All SAEs must be reported whether 
or not they are considered causally related to study treatment (SBT6050, T-DXd, tucatinib, 
trastuzumab, and/or capecitabine). Serious adverse event forms will be completed, and the 
information collected will include subject number, a narrative description of the event, and an 
assessment by the Investigator as to the severity of the event and relationship to study drug. 
Follow-up information on the SAE may be requested by the Sponsor or medical monitor. 
If there are serious, unexpected adverse drug reactions associated with the use of study treatment, 
the Sponsor will notify the appropriate regulatory agency(ies) and all participating Investigators 
on an expedited basis. The local institutional review board/independent ethics committee 
(IRB/IEC) will be promptly notified based on local regulations where required by the IRB/IEC 
of all serious, unexpected adverse drug reactions involving risk to human subjects. 
Progression of the Underlying Cancer 
Disease progression or death due to the primary disease under study should not be reported as an 
AE (or an SAE) if clearly consistent with the suspected progression of the underlying cancer as 


 
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defined by RECIST Version 1.1 (see Section 11.4); however, disease progression or death will 
be collected as an outcome or reason for discontinuation, as appropriate. Adverse events (or 
SAEs) considered to be complications of disease progression should be reported. 
Clinical symptoms of progression may be reported as AEs if the symptoms cannot be determined 
as exclusively due to the progression of the subject’s underlying disease or does not fit the 
expected pattern of progression for the disease. The specific disease or clinical manifestation of 
the progression (eg, malignant pleural effusion, spinal bone metastases, lymphadenopathy from 
underlying malignancy, brain metastases) should be recorded. 
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE. 
Adverse Events Associated with SBT6050 Administration 
For AEs suspected to be associated with the study drug, each sign and symptom should be 
recorded as an individual AE (including in instances where multiple signs or symptoms occur). If 
signs and symptoms are consistent with a specific syndrome (eg, “cytokine release syndrome”), 
this should be reported in addition to individual signs and symptoms. 
6.9.3 Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be reported 
as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (eg, dose modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• Is clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
When recording an AE resulting from a laboratory abnormality, the resulting medical condition 
rather than the abnormality itself should be recorded (eg, record “anemia” rather than “low 
hemoglobin”).  
If a clinically significant laboratory abnormality is a sign of a disease (eg, ALP and bilirubin 5 × 
ULN associated with cholecystitis), record only the diagnosis (ie, cholecystitis), if known, on the 
AE eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease, the abnormality itself 
should be recorded on the AE eCRF, along with a descriptor indicating if the test result is above 
or below the normal range. 


 
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Pregnancy 
Pregnancy is neither an AE nor an SAE, unless a complication relating to the pregnancy occurs 
(eg, spontaneous abortion, which may qualify as an SAE).  
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject or partner of a male subject occurring while the subject is on 
study treatment, or within 30 days of the subject’s last dose of study treatment, are considered 
immediately reportable events. If a female partner of a male subject taking investigational 
product becomes pregnant, the male subject taking study treatment should notify the 
Investigator, and the pregnant female partner should be advised to call her healthcare provider 
immediately. In pregnant female subjects, study treatment is to be discontinued immediately. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported immediately 
using the Pregnancy Report form. The Investigator must follow-up and document the course and 
outcome of all pregnancies even if the subject was discontinued from the study or if the subject 
has completed the study. The female subject or partner of a male subject should receive any 
necessary counseling regarding the risks of continuing the pregnancy and the possible effects on 
the fetus. Monitoring should continue until conclusion of the pregnancy. 
All outcomes of pregnancy (from a female subject or the sexual partner of a male subject) must 
be reported by the Investigator to the Sponsor or medical monitor on a Pregnancy Outcome 
Report form within 30 days after he/she has gained knowledge of the delivery or elective 
abortion.  
Any SAE that occurs during pregnancy must be recorded on the SAE report form (eg, maternal 
serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, birth defect) and reported within 24 hours in accordance 
with the procedure for reporting SAEs. 
6.9.4 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through 30 days 
after the last dose of study treatment. However, all AEs are to be recorded from the time of 
informed consent. All SAEs that occur after the safety reporting period and are considered study 
treatment-related in the opinion of the Investigator should also be reported to the Sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the Investigator, or the 
subject dies or withdraws consent. All non-serious AEs will be followed through the safety 
reporting period. Certain non-serious AEs of interest may be followed until resolution, return to 
baseline, or study closure. 
6.9.5 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, Investigators are to report the event to the 
Sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a minimum, 
the following should be included: 




 
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7. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
7.1 Site Training and Monitoring Procedures 
The study will be conducted in accordance with GCP, ICH guidelines, and the appropriate 
regulatory requirement(s). The Investigator will be thoroughly familiar with the appropriate use 
of the study drug as described in the protocol, Investigator’s Brochure, and pharmacy manual. 
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study, and retained according to the appropriate regulations. 
The study will be monitored by the Sponsor or its designee. Monitoring will be done virtually or 
on site by the Sponsor or designee and will include review of the source documents/eCRFs for 
completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed. The review of medical records will be performed in a 
manner to ensure that subject confidentiality is maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, telephone, e-mail, and fax). 
All unused study drug and other study materials should be destroyed or returned to the Sponsor 
or designee after the study has been completed, as directed by the Sponsor. 
7.2 Data Management Procedures 
Source documents and eCRFs will be completed for each study subject, including subjects who 
provide informed consent but do not meet study eligibility. It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s source 
documents and eCRF. The source document and eCRF should indicate the subject’s participation 
in the study and should document the dates and details of study procedures, AEs, and subject 
status. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be provided for all 
missing data. 
Paper and digital source documents are to be retained to enable reconstruction and evaluation of 
the clinical study. Source documents include the hospital subject files and any study-related 
worksheets provided by the Sponsor. 
The Investigator must sign and date the Investigator’s Statement at the end of the eCRF to 
endorse the recorded data. 
7.3 Access to Source Data 
Regulatory authorities, the IEC/IRB, and/or the Sponsor’s clinical quality assurance group or 
designee may request access to all source documents, eCRFs, and other study documentation for 


 
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an on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
7.4 Accuracy and Reliability of Data 
To assure the accuracy and reliability of data, steps to be taken include: 
• The selection of qualified Investigators and appropriate study sites/centers. 
• Review of protocol procedures with Investigators and associated personnel prior to the 
study. 
• Periodic monitoring visits by designated monitor(s) (see Section 7.1). 
• CRFs will be reviewed for accuracy and completeness during monitoring visits to the 
study sites/centers. Any discrepancies will be resolved with the Investigator or designees 
as appropriate. 
7.5 Quality Assurance Procedures 
The Sponsor or its designee may conduct audits at the clinical site/center or other study-related 
facilities and organizations. Audit reports will be retained by the Sponsor as part of the written 
record. 
7.6 Data Handling and Record Keeping 
7.6.1 Data Handling 
All data for the subjects recruited for the trial will be entered onto the eCRFs via an electronic 
data capture (EDC) system provided by the Sponsor or designee. Only authorized staff may enter 
data onto the eCRFs. If an entry error is made, the corrections to the eCRFs will be made 
according to eCRF guidelines by an authorized member of the site staff. 
Electronic CRFs (eCRFs) will be checked for correctness against source document data by the 
Sponsor’s monitor. If any entries into the eCRF are incorrect or incomplete, the monitor will ask 
the Investigator or the study site staff to make appropriate corrections, and the corrected eCRF 
will again be reviewed for completeness and consistency. Data entry will be reviewed with 
programmed logic checks and electronic data queries will be generated to verify potential 
discrepancies in the eCRF system. Authorized site staff will be asked to respond to all electronic 
queries according to the eCRF guidelines. 
7.6.2 Investigator Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor must be notified in writing if a custodial change occurs. 


 
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8. 
STATISTICAL CONSIDERATIONS 
A brief description of key analyses is provided below; a full description of the statistical 
evaluations, general considerations, and procedures for handling missing data will be provided in 
the Statistical Analysis Plan (SAP). All analyses will be performed by cohort within each part 
(dose escalation and dose expansion). 
A change to the data analysis methods described in the protocol will require a protocol 
amendment only if it alters site conduct (eg, adding safety assessments to further define the 
course of TEAEs). The SAP will be finalized prior to database lock. Any changes to the methods 
described in the final SAP will be described and justified in the clinical study report. 
8.1 Determination of Sample Size 
Up to approximately 328 subjects will be enrolled across this 2-part study as described in 
Section 3.1 and presented in Figure 1 (approximately 12 subjects in each of the four dose-
escalation plans and approximately 40 subjects in each of the seven expansion cohorts). The 
expansion cohort sample size is consistent with FDA Guidance for Industry, Expansion Cohorts: 
Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and 
Biologics, 2018. Accessed: Aug 19, 2021. 
During dose expansion in both Part 1 and Part 2, for each tumor-specific cohort, the ORR along 
with the corresponding two-sided 80% confidence intervals will be evaluated to assess proof-of-
concept for SBT6050 when combined with two dose levels of T-DXd (Part 1) or tucatinib and 
trastuzumab ± capecitabine (Part 2). Other signs of potential activity, including duration of 
response and clinical benefit rate (CBR), as well as the overall benefit/risk will also be factored 
into the final efficacy conclusions. Because the study is evaluating SBT6050 in combination with 
approved therapies, no early futility analyses are planned. 
Table 6 provides the ORR estimates that must be observed in each tumor-specific cohort in 
Part 1 so that the lower 80% confidence bound will rule out the response rate associated with  
T-DXd alone. For each cohort, the power to observe the ORR estimate is also shown under a 
15% absolute improvement in ORR for SBT6050 with T-DXd relative to the historical ORR for 
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Table 6: 
Historical and target ORR estimates with associated precision and power calculations 
under varying response probabilities for SBT6050 combined with T-DXd 
Cohort 
Historical ORR for T-DXd alone 
(p0) 
SBT6050 
with T-
DXd ORR 
(p1) 
Lower CI 
bound 
approximately 
above p0 
Power under assumed 
true SBT6050 with T-
DXd ORR (π1) 
π1a 
Power 
Cohort A 
(HER2+ BC) 
61% (Modi 2020) 
29/40 
(73%) 
80% CI: 
(62%, 82%) 
76% 
76% 
Cohort B 
(HER2+ CRC) 
45.3% (Yoshino 2021) 
23/40 
(58%) 
80% CI: 
(46%, 68%) 
60% 
69% 
Cohort C 
(HER2-
expressing 
NSCLC) 
24.5% (Nakagawa 2020) 
14/40 
(35%) 
80% CI: 
(25%, 46%) 
40% 
79% 
Cohort D 
(HER2+ 
gastric/GEJ 
cancer) 
38% (van Cutsem 2021) 
20/40 
(50%) 
80% CI: 
(39%, 61%) 
53% 
71% 
CI = confidence interval; CRC = colorectal cancer; BC = breast cancer; GEJ = gastroesophageal junction; NSCLC = non-small-cell lung cancer; 
ORR = objective response rate; T-DXd = trastuzumab deruxtecan 
aTrue SBT6050 with T-DXd ORR is assumed to be 15% greater than historical ORR for T-DXd alone (absolute difference). 
Table 7 provides the ORR estimates that must be observed in each dose expansion cohort in 
(Part 2) so that the lower 80% confidence bound will rule out the response rate associated with 
tucatinib and trastuzumab ± capecitabine. For each cohort, the power to observe the ORR 
estimate is also shown under a 15% absolute improvement in ORR for the SBT6050 combination 
regimen relative to the historical ORR for the backbone regimen. 
Table 7: 
Historical and target ORR estimates with associated precision and power calculations 
under varying response probabilities for SBT6050 combined with tucatinib and 
trastuzumab ± capecitabine 
Cohort 
Historical 
ORR for 
tucatinib 
and 
trastuzumab 
+ 
capecitabine 
(p0) 
Historical 
ORR for 
tucatinib 
and 
trastuzumab 
(p0) 
SBT6050 
with T-DXd 
ORR (p1) 
Lower CI 
bound 
approximately 
above p0 
Power under assumed true 
SBT6050 with tucatinib 
and trastuzumab ± 
capecitabine ORR (π1) 
π1a 
Power 
Cohort E 
(HER2+ BC) 
41% 
(Murthy 
2020) 
N/A 
21/40 (53%) 
80% CI: 
(41%, 64%) 
56% 
73% 
Cohort F 
(HER2+ BC) 
N/A 
40% 
21/40 (53%) 
80% CI: 
(41%, 64%) 
55% 
68% 
Cohort G 
(HER2+ CRC) 
N/A 
52% 
26/40 (65%) 
80% CI: 
(54%, 75%) 
67% 
67% 
CI = confidence interval; CRC = colorectal cancer; BC = breast cancer; N/A = not applicable 
aTrue SBT6050 combined with tucatinib and trastuzumab ± capecitabine ORR is assumed to be 15% greater than historical ORR for tucatinib and 
trastuzumab ± capecitabine (absolute difference). 


 
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8.2 Analysis Populations 
The following subject populations will be analyzed: 
• Enrolled population: all subjects who sign informed consent 
• All-Treated population: all subjects who receive at least one dose of study treatment 
• PK-Evaluable population: all subjects who receive at least one dose of study treatment 
and have concentration-time data available 
• DLT-Evaluable population: all subjects who receive at least one dose of study treatment 
and have completed the 21-day DLT evaluation period or discontinue study drug due to 
AEs meeting DLT criteria. 
• Efficacy-Evaluable population: all subjects who receive at least 1 dose of the study 
treatment and have an evaluable baseline and post baseline response assessment per 
RECIST Version 1.1 or who discontinue prior to disease assessment due to clinical 
progression of disease. 
• Per Protocol population (for sensitivity analysis only): all subjects who receive at least 
one dose of study treatment, have an evaluable baseline and post baseline response 
assessment per RECIST Version 1.1, and have no major protocol deviations that would 
exclude them from the population 
Additional analysis sets of subjects may be defined in the SAP. 
8.3 Efficacy Analyses 
All efficacy analyses will be performed for all treated subjects by cohort. Summary analyses will 
be performed in subjects treated at the RP2D for the given cohort; listings will be produced for 
subjects treated at other dose levels. 
8.3.1 Dose Expansion Cohorts 
ORR is defined as the proportion of treated subjects who achieve a best response of CR or PR. 
To evaluate proof-of-concept for an efficacy signal, a two-sided 80% exact CI as well as a 95% 
exact CI will be calculated for ORR using the Clopper-Pearson method. Best response will be 
summarized by response category. 
CBR is defined as the proportion of treated subjects who achieve a best response of CR or PR or 
have a best response of SD with a duration of ≥ 6 months from initiation of study treatment. 
CBR will also contribute to evaluation of efficacy proof-of-concept. A two-sided 80% exact CI 
as well as a 95% exact CI will be calculated for CBR using the Clopper-Pearson method. 
PFS is defined as the time from the first dose of study therapy to the date of documented 
progression or death, whichever occurs first. Subjects who are alive and progression-free will be 
censored on the date of last evaluable efficacy assessment. Subjects who receive subsequent anti-
cancer therapy prior to documented progression will be censored on the date of the last evaluable 
efficacy assessment on or prior to the subsequent anti-cancer therapy start date. 
OS is defined as the time from first dose of study therapy to the date of death due to any cause. 
Subjects who are alive will be censored on the date of last contact. 




 
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A given expansion cohort will be reviewed when approximately 40 subjects have received at 
least one dose of study therapy and have at least one post-baseline efficacy evaluation. The 
Sponsor will assess whether the efficacy and safety data support proof-of-concept for the cohort. 
The Sponsor may also periodically evaluate available data during the expansion enrollment. 
A primary analysis for the study may be conducted after a minimum follow-up of 4 months after 
the last subject’s first visit or when the last subject has progressed, whichever occurs sooner 
among the last dose expansion cohort to fully enroll. The primary analysis will be the basis for 
the CSR. 
Subjects may continue to be followed for long-term efficacy and safety after the primary 
analysis. In this case, the final analysis will be conducted at the end of the trial and will be 
summarized in a CSR addendum. 
8.7.1 Interim Analyses 
During dose escalation in Part 1 and Part 2, an SMC will convene periodically during the study 
to monitor the trial for safety. An ongoing review of SAEs in both parts of the study and all 
cohorts will also be conducted by the Sponsor. 
Because no formal statistical inference is planned, adjustment to type 1 error is not required. 


 
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9. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6(R2), Good Clinical Practice: Integrated 
addendum to ICH E6(R1), 2018. Accessed: Aug 19, 2021; FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2003), and all applicable regulatory requirements. 
9.1 Informed Consent 
The Investigator at each site will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk, and benefit of the study. Subjects 
must also be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
After the study has been fully explained, written informed consent will be obtained from either 
the subject or his/her guardian or legal representative prior to study participation.  
The subject’s signed and dated informed consent must be obtained before conducting any study 
related procedures. The Investigator must maintain the original, signed consent form. A copy of 
the signed form must be given to the subject. 
The method of obtaining and documenting the informed consent and the contents of the consent 
will comply with ICH-GCP and all applicable regulatory requirement(s). 
9.2 Ethical Review 
The Investigator must obtain the IRB/IEC approval for the investigation and must submit written 
documentation of the approval to the Sponsor before he or she can enroll any subject into the 
study. The IRB/IEC will review all appropriate study documentation to safeguard the rights, 
safety, and wellbeing of the subjects. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, Investigator’s Brochure, informed consent, 
advertisements (if applicable), written information given to the subjects, safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC. The 
IRB/IEC is to be notified of any amendment to the protocol in accordance with local 
requirements. Progress reports and notifications of serious unexpected adverse drug reactions are 
to be provided to the IRB/IEC according to local regulations and guidelines. 
9.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in the 
applicable guidelines on good clinical practice, and all applicable local and/or regional laws, 
rules, and regulations. 
9.3.1 Investigator Information 
The contact information and qualifications of the principal Investigator and subinvestigators and 
the name and address of the research facilities are included in the Investigator file. 


 
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9.3.2 Protocol Amendments and Study Termination 
The Investigator will conduct the study in compliance with the protocol. Modifications to the 
protocol should not be made without agreement of both the Investigator and the Sponsor. 
Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
subjects. The IRB/IEC may provide, if applicable, where regulatory authority(ies) permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The Sponsor or designee will submit all 
protocol modifications to the regulatory authority(ies) in accordance with the governing 
regulations.  
Any Investigator-initiated changes to the protocol (except for changes to eliminate an immediate 
hazard to a study subject) must be approved by the Sponsor prior to seeking approval from the 
IRB/IEC and prior to implementation. Any departures from the protocol must be fully 
documented in the source documents/eCRF. 
The Sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
9.4 Study Documentation, Privacy, and Records Retention 
To maintain subject privacy, all source documents/eCRFs, study drug accountability records, 
study reports and communications will identify the subject by the assigned Subject Number. The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered on 
the source documents/eCRFs and to audit the data collection process. The subject’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
In compliance with local and/or regional regulations, this trial may be registered and trial results 
may be posted on public registries, such as ClinicalTrials.gov. 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
All information regarding SBT6050 supplied by the Sponsor or designee to the Investigator is 
privileged and confidential information. The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without written consent from the 
Sponsor. It is understood that there is an obligation to provide the Sponsor with complete data 
obtained during the study. The information obtained from the clinical study will be used towards 
the development of SBT6050 and may be disclosed to regulatory authority(ies), other 
Investigators, corporate partners, or consultants as required. 
Details regarding payments by the Sponsor to Investigators and institutions conducting the trial, 
requirements for Investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical study agreement. 


 
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A. Miller, R. Yelensky, Y. Li, J. D. Allen, E. V. Sigal, D. Wholley, C. C. Sigman, G. M. 
Blumenthal, S. Malik, G. J. Kelloff, J. S. Abrams, C. D. Blanke, and V. A. 
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Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: 
SWOG S1400', Clin Cancer Res, 21: 1514-24. 
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Freiwald, J. Fan, B. Wang, V. K. Chand, and H. J. M. Groen. 2017. 'Continued use of 
afatinib with the addition of cetuximab after progression on afatinib in patients with 
EGFR mutation-positive non-small-cell lung cancer and acquired resistance to gefitinib 
or erlotinib', Lung Cancer, 113: 51-58. 
Krop, I. E., S. B. Kim, A. Gonzalez-Martin, P. M. LoRusso, J. M. Ferrero, M. Smitt, R. Yu, A. 
C. Leung, H. Wildiers, and Th Resa study collaborators. 2014. 'Trastuzumab emtansine 
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cancer (TH3RESA): a randomised, open-label, phase 3 trial', Lancet Oncol, 15: 689-99. 
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Diebold, E. Felip, I. Rouquette, J. D. Milia, and O. Gautschi. 2013. 'Lung cancer that 
harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives', J 
Clin Oncol, 31: 1997-2003. 
Meric-Bernstam, F., A. M. Johnson, E. E. I. Dumbrava, K. Raghav, K. Balaji, M. Bhatt, R. K. 
Murthy, J. Rodon, and S. A. Piha-Paul. 2019. 'Advances in HER2-Targeted Therapy: 
Novel Agents and Opportunities Beyond Breast and Gastric Cancer', Clin Cancer Res, 
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Modi, S., C. Saura, T. Yamashita, Y. H. Park, S. B. Kim, K. Tamura, F. Andre, H. Iwata, Y. Ito, 
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S. A. Hurvitz, J. Cortes, C. Lee, S. Chen, L. Zhang, J. Shahidi, A. Yver, I. Krop, and D. 
ESTINY-Breast01 Investigators. 2020. 'Trastuzumab Deruxtecan in Previously Treated 
HER2-Positive Breast Cancer', N Engl J Med, 382: 610-21. 
Murthy, R. K., S. Loi, A. Okines, E. Paplomata, E. Hamilton, S. A. Hurvitz, N. U. Lin, V. 
Borges, V. Abramson, C. Anders, P. L. Bedard, M. Oliveira, E. Jakobsen, T. Bachelot, S. 
S. Shachar, V. Muller, S. Braga, F. P. Duhoux, R. Greil, D. Cameron, L. A. Carey, G. 
Curigliano, K. Gelmon, G. Hortobagyi, I. Krop, S. Loibl, M. Pegram, D. Slamon, M. C. 
Palanca-Wessels, L. Walker, W. Feng, and E. P. Winer. 2020. 'Tucatinib, Trastuzumab, 
and Capecitabine for HER2-Positive Metastatic Breast Cancer', N Engl J Med, 382: 597-
609. 
Nakagawa, K., NM, Felip E., et al. . 2020. 'Trastuzumab deruxtecan in her2-overexpressing 
metastatic non-small cell lung cancer: Interim results of destiny-lung01.', Presented at: 
2020 World Conference on Lung Cancer Singapore(Virtual). 
Pegram, M. D., G. E. Konecny, C. O'Callaghan, M. Beryt, R. Pietras, and D. J. Slamon. 2004. 
'Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment 
of breast cancer', J Natl Cancer Inst, 96: 739-49. 
Pillai, R. N., M. Behera, L. D. Berry, M. R. Rossi, M. G. Kris, B. E. Johnson, P. A. Bunn, S. S. 
Ramalingam, and F. R. Khuri. 2017. 'HER2 mutations in lung adenocarcinomas: A report 
from the Lung Cancer Mutation Consortium', Cancer, 123: 4099-105. 
Ponce, R. 2011. 'ICH S9: Developing anticancer drugs, one year later', Toxicol Pathol, 39: 913-5. 
Robert, N., B. Leyland-Jones, L. Asmar, R. Belt, D. Ilegbodu, D. Loesch, R. Raju, E. Valentine, 
R. Sayre, M. Cobleigh, K. Albain, C. McCullough, L. Fuchs, and D. Slamon. 2006. 
'Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with 
trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast 
cancer', J Clin Oncol, 24: 2786-92. 
Ross, J. S., M. Fakih, S. M. Ali, J. A. Elvin, A. B. Schrock, J. Suh, J. A. Vergilio, S. 
Ramkissoon, E. Severson, S. Daniel, D. Fabrizio, G. Frampton, J. Sun, V. A. Miller, P. J. 
Stephens, and L. M. Gay. 2018. 'Targeting HER2 in colorectal cancer: The landscape of 
amplification and short variant mutations in ERBB2 and ERBB3', Cancer, 124: 1358-73. 
Rostoker, G., P. Andrivet, I. Pham, M. Griuncelli, and S. Adnot. 2007. 'A modified Cockcroft-
Gault formula taking into account the body surface area gives a more accurate estimation 
of the glomerular filtration rate', J Nephrol, 20: 576-85. 
Ruschoff, J. 2012. 'Adenocarcinoma of the GEJ: gastric or oesophageal cancer?', Recent Results 
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Sartore-Bianchi, A., L. Trusolino, C. Martino, K. Bencardino, S. Lonardi, F. Bergamo, V. 
Zagonel, F. Leone, I. Depetris, E. Martinelli, T. Troiani, F. Ciardiello, P. Racca, A. 
Bertotti, G. Siravegna, V. Torri, A. Amatu, S. Ghezzi, G. Marrapese, L. Palmeri, E. 
Valtorta, A. Cassingena, C. Lauricella, A. Vanzulli, D. Regge, S. Veronese, P. M. 
Comoglio, A. Bardelli, S. Marsoni, and S. Siena. 2016. 'Dual-targeted therapy with 
trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-
positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, 
open-label, phase 2 trial', Lancet Oncol, 17: 738-46. 
Shen, Y., T. Fujii, N. T. Ueno, D. Tripathy, N. Fu, H. Zhou, J. Ning, and L. Xiao. 2019. 
'Comparative efficacy of adjuvant trastuzumab-containing chemotherapies for patients 
with early HER2-positive primary breast cancer: a network meta-analysis', Breast Cancer 
Res Treat, 173: 1-9. 
Siena, S., M. Di Bartolomeo, K. Raghav, T. Masuishi, F. Loupakis, H. Kawakami, K. 
Yamaguchi, T. Nishina, M. Fakih, E. Elez, J. Rodriguez, F. Ciardiello, Y. Komatsu, T. 
Esaki, K. Chung, Z. Wainberg, A. Sartore-Bianchi, K. Saxena, E. Yamamoto, E. Bako, 
Y. Okuda, J. Shahidi, A. Grothey, T. Yoshino, and Destiny-Crc investigators. 2021. 
'Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic 
colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial', Lancet 
Oncol, 22: 779-89. 
Slamon, D. J., B. Leyland-Jones, S. Shak, H. Fuchs, V. Paton, A. Bajamonde, T. Fleming, W. 
Eiermann, J. Wolter, M. Pegram, J. Baselga, and L. Norton. 2001. 'Use of chemotherapy 
plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses 
HER2', N Engl J Med, 344: 783-92. 
Strickler, John H., Kimmie Ng, Andrea Cercek, Christos Fountzilas, Federico Augusto Sanchez, 
Joleen M. Hubbard, Christina Wu, Salvatore Siena, Josep Tabernero, Eric Van Cutsem, 
Adel Kardosh, Anwaar Saeed, Thierry Andre, Michael Stecher, Maria Corinna Palanca-
Wessels, and Tanios S. Bekaii-Saab. 2021. 'MOUNTAINEER: open-label, phase II study 
of tucatinib combined with trastuzumab for HER2-positive metastatic colorectal cancer 
(SGNTUC-017, trial in progress)', Journal of Clinical Oncology, 39: TPS153-TPS53. 
TUKYSA. 2020. 'TUKYSA Prescribing Information', Seagen Inc. 


 
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Valtorta, E., C. Martino, A. Sartore-Bianchi, F. Penaullt-Llorca, G. Viale, M. Risio, M. Rugge, 
W. Grigioni, K. Bencardino, S. Lonardi, V. Zagonel, F. Leone, J. Noe, F. Ciardiello, C. 
Pinto, R. Labianca, S. Mosconi, C. Graiff, G. Aprile, B. Frau, C. Garufi, F. Loupakis, P. 
Racca, G. Tonini, C. Lauricella, S. Veronese, M. Truini, S. Siena, S. Marsoni, and M. 
Gambacorta. 2015. 'Assessment of a HER2 scoring system for colorectal cancer: results 
from a validation study', Mod Pathol, 28: 1481-91. 
Van Cutsem, E., di Bartolomeo, M., Smyth, E., Chau, I., Park, H., Siena, S., Lonardi, S., 
Wainberg, Z. A., Ajani, J., Chao, J., Seraj, J., Kawaguchi, Y., Qin, A., Singh, J. 
Meinhardt, G., and Ku, G. Primary analysis of a phase 2, open-label, single arm trial of 
trastuzumab deruxtecan in Western patients with HER2-positive unresectable or 
metastatic gastric or gastroesophageal junction cancer on or after a trastuzumab-
containing regimen. Presented at: European Society for Medical Oncology; Sep 17, 2021; 
Virtual Congress. 
Verma, S., D. Miles, L. Gianni, I. E. Krop, M. Welslau, J. Baselga, M. Pegram, D. Y. Oh, V. 
Dieras, E. Guardino, L. Fang, M. W. Lu, S. Olsen, K. Blackwell, and Emilia Study 
Group. 2012. 'Trastuzumab emtansine for HER2-positive advanced breast cancer', N Engl 
J Med, 367: 1783-91. 
Wilke, H., K. Muro, E. Van Cutsem, S. C. Oh, G. Bodoky, Y. Shimada, S. Hironaka, N. 
Sugimoto, O. Lipatov, T. Y. Kim, D. Cunningham, P. Rougier, Y. Komatsu, J. Ajani, M. 
Emig, R. Carlesi, D. Ferry, K. Chandrawansa, J. D. Schwartz, A. Ohtsu, and Rainbow 
Study Group. 2014. 'Ramucirumab plus paclitaxel versus placebo plus paclitaxel in 
patients with previously treated advanced gastric or gastro-oesophageal junction 
adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial', Lancet Oncol, 
15: 1224-35. 
Wolff, H. A., C. R. Wolff, C. F. Hess, K. Jung, S. Sennhenn-Kirchner, M. Hinterthaner, A. 
Muller-Dornieden, W. Korber, K. Marten-Engelke, R. Roedel, H. Christiansen, and C. 
Engelke. 2013. 'Second primary malignancies in head and neck cancer patients: high 
prevalence of curable-stage disease', Strahlenther Onkol, 189: 874-80. 
XELODA. 2021. 'XELODA Prescribing Information', Genentech, Inc. 
Yoshino, T. Di Bartolomeo, M. Raghav KPS, Masuishi T, Loupakis F, Kawakami H, Yamaguchi 
K, Nishina T, Wainberg ZA, Elez E, Rodriguez J, Fakih M, Ciardiello F, Saxena K, 
Kobayashi K, Bako E, Okuda Y, Meinhardt G, Grothey A and Siena S. 2021. 
'Trastuzumab deruxtecan (t-dxd; ds-8201) in patients (pts) with her2-expressing 
metastatic colorectal cancer (mcrc): Final results from a phase 2, multicenter, open-label 
study (destiny-crc01).', Journal of Clinical Oncology, 39: 3505-05. 
 
 


 
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11. 
APPENDICES 
 






 
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stimulating hormone, and troponin. Creatinine clearance, only required for eligibility criteria at Screening/Baseline, will be calculated using the Cockcroft-Gault 
formula. 
gThyroid panel consists of triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). 
hCoagulation panel consists of PT/international normalized ratio (INR) and PTT (or, depending on institutional standard, aPTT). 
iRequired only if not performed in the previous 12 weeks. 
jVital signs will be taken predose SBT6050 and postdose 15, 30, 45, 60 minutes (+/-15 minutes) SBT6050 and then immediately following the end of the T-DXD 
infusion (+15 minutes) on dosing days. 
kRequired for all subjects with breast cancer or NSCLC and for subjects with gastric or GEJ cancer or CRC who have a history of CNS metastases or have signs 
or symptoms suggestive of CNS metastasis. 
 
mPostdose measurements should be taken 4 hours ±30 minutes after SBT6050 dosing. 
nCollect Day 1 predose at Cycles 4, 6, 8, 11 and every 3 cycles thereafter. 
oIf a subject stops treatment with SBT6050, no further PK sample is needed. 
pSee Section 5.1 for a description of treatments to be administered during the study. SBT6050 should be administered first, followed by T-DXd. T-DXd infusion 
should begin at least 15 minutes after the injection of SBT6050. 
qTumor assessment by CT, PET/CT (if diagnostic-quality CT scan included), or MRI. Subjects who experience an objective response (ie, tumor reduction) 
should have a confirmatory assessment performed approximately 4 weeks after the initial response. 
rIf not performed in the previous 6 weeks. 
sAn archived tumor tissue may be submitted for baseline/screening tests for some subjects (see Section 6.1). 
 
 
 
 






 
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also be performed. 
fChemistry panel consists of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, calcium, phosphate, magnesium, creatinine, total protein, albumin, 
glucose, total and direct bilirubin, amylase, alkaline phosphatase (ALP), ALT, AST, lactate dehydrogenase, γ glutamyl transferase, lipase, triglycerides, thyroid-
stimulating hormone, and troponin. Creatinine clearance, only required for eligibility criteria at Screening/Baseline, will be calculated using the Cockcroft-Gault 
formula. 
gThyroid panel consists of triiodothyronine (T3) or free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). 
hCoagulation panel consists of PT/international normalized ratio (INR) and PTT (or, depending on institutional standard, aPTT). 
iRequired only if not performed in the previous 12 weeks. 
jVital signs will be taken predose SBT6050 and postdose 15, 30, 45, 60 minutes (+/-15 minutes) SBT6050 and then immediately following the end of the 
trastuzumab infusion (+15 minutes) on dosing days. 
kRequired for all subjects with breast cancer and for subjects with CRC who have a history of CNS metastases or have signs or symptoms suggestive of CNS 
metastasis. 
 
mPostdose measurements should be taken 4 hours ±30 minutes after SBT6050 dosing. 
nCollect Day 1 predose at Cycles 4, 6, 8, and 11, then every 3 cycles thereafter. 
oIf a subject stops treatment with SBT6050, no further PK sample is needed. 
pSee Section 5.1 for a description of treatments to be administered during the study. SBT6050 should be administered first, followed by trastuzumab. 
Trastuzumab infusion should begin at least 15 minutes after the injection of SBT6050. At Cycle 1/Day 1, tucatinib and capecitabine (if applicable) should also be 
taken after SBT6050 and trastuzumab in the clinic. On Day 1 of each cycle, study staff should review tucatinib and capecitabine (if applicable) compliance from 
previous cycle. 
qTumor assessment by CT, PET/CT (if diagnostic-quality CT scan included), or MRI. Subjects who experience an objective response (ie, tumor reduction) 
should have a confirmatory assessment performed approximately 4 weeks after the initial response. 
rIf not performed in the previous 6 weeks. 
sAn archived tumor tissue may be submitted for baseline/screening tests for some subjects (see Section 6.1). 
 
 
 


 
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11.3 Common Terminology Criteria for Adverse Events 
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5
Quick Reference 8.5x11.pdf 


 
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11.4 Response Evaluation Criteria in Solid Tumors (RECIST), Version 
1.1 
Response assessment for this protocol will be performed according to RECIST Version 
1.1 (Eisenhauer 2009) as described below. 
Evaluation of Target Lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
Partial Response (PR) 
At least 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease 
At least 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute of at least 5 mm. Note that the 
appearance of one or more new lesions is also considered 
progressions. 
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease, taking as 
reference he smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
Complete Response 
(CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in 
complete clinical response. 
Non-CR/Non-
progressive disease 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal 
progression should not normally trump target lesion status. It 
must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference the smallest measurements 
recorded for progressive disease since the treatment started). The patient’s best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Subjects with Measurable Disease (ie, Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Responsea 
Best Overall 
Response when 
Confirmation 
is Requiredb 
CR 
CR 
No 
 CR 
>4 weeks 
confirmationc 
CR 
Non-CR/ 
Non-progressive 
disease 
No 
PR 
>4 weeks 
confirmationc 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
progressive 
disease/ 
Not evaluated 
No 
PR 
Stable disease 
Non-CR/Non-
progressive 
disease/ 
Not evaluated 
No 
Stable disease 
Documented at 
least once 
>4 weeks from 
baselinec 
Progressive 
disease 
Any 
Yes or No 
Progressive 
disease 
No prior stable 
disease, PR, or 
CR 
Any 
Progressive 
diseased 
Yes or No 
Progressive 
disease 
Any 
Any 
Yes 
Progressive 
disease 
a 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
b 
See RECIST Version 1.1 for further details for evidence of a new lesion. 
c 
Only for non-randomized studies with response as primary endpoint. 
d 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression.  


 
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For Subjects with Non-Measurable Disease (ie, Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
 CR 
Non-CR/Non-progressive 
disease 
No 
Non-CR/Non-progressive 
diseasea 
Not all evaluated 
No 
Not evaluated 
Unequivocal progressive disease 
Yes or No 
Progressive disease 
Any 
Yes 
Progressive disease 
a 
Non-CR/non-progressive disease is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some studies so to assign this 
category when no lesions can be measured is not advised. 
Duration of Response 
Duration of overall 
response 
The duration of overall response is measured from the 
time measurement criteria are met for CR and PR 
(whichever is recorded first) until the first date that 
recurrent or progressive disease is objectively 
documented (taking as reference the smallest 
measurements for progressive disease since the treatment 
started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first 
date that progressive disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including baseline measurements. 


 
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11.5 Eastern Cooperative Oncology Group Performance Status 
 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of 
a light or sedentary nature, ie, light housework, office work 
1 
Ambulatory and capable of self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair or more than 50% of waking 
hours. 
3 
 
Completely disabled. Cannot carry on any self-care. Totally confined to be or chair 
4 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982). 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6): 649-
655. 


 
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11.6 Cockroft-Gault Equation 
Cockcroft-Gault equation (Rostoker 2007) = [(140 – age) × weight in kg × (0.85 if 
female)] ÷ (72 × plasma creatinine in mg/dL) 
 


 
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11.7 Guidance on Contraception 
Female Subjects 
A female subject is considered of childbearing potential if she is anatomically and 
physiologically capable of becoming pregnant and will be or could possibly be sexually 
active with a male partner while undergoing study treatment with the possibility of 
posing harm to a fetus. 
Female subjects of childbearing potential must agree to abstain from sexual intercourse or 
to use a highly effective form of contraception from the time of giving informed consent, 
during the study, and for up to 7 months following the last dose of study treatment.  
Examples of highly effective contraceptive methods (methods with a failure rate of <1% 
per year) include bilateral tubal ligation; male sterilization; established, proper use of 
hormonal contraceptives that inhibit ovulation; hormone-releasing intrauterine device 
(IUD); and copper IUDs. The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Male Subjects 
A male subject is considered of sexual reproductive potential if he is anatomically and 
physiologically capable of causing a pregnancy in a female partner and will be or could 
possibly be sexually active with a female partner (who is or may become pregnant) while 
undergoing study treatment with the possibility of posing harm to a fetus. 
Males with partners of reproductive potential must agree to commit to either continued 
abstinence from sexual intercourse, or that they or their partners will use at least 2 
effective contraceptive methods (including 1 barrier method) when engaging in 
reproductive sexual activity throughout the study, and will avoid conceiving for up to 2 
months after the last dose of study treatment. 


 
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11.8 Drug Interactions Table of Substrates, Inhibitors, and Inducers 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
 


 
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11.9 Investigator Statement 
I understand that all documentation provided to me by Silverback Therapeutics, Inc. or its 
designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence. This documentation includes the study protocol, 
investigator brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board/Ethics Committee. No changes will be made to the study 
protocol without the prior written approval of Silverback Therapeutics, Inc. and the 
Institutional Review Board/Ethics Committee, except where necessary to eliminate an 
immediate hazard to the subject. 
I have read, understood, and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
 
 
Investigator Name 
 
Investigator Signature 
 
Date 
 
 
 
 
Investigational site or name of institution and address (printed) 
 


 
SBT6050-201 
Clinical Protocol 
Version A01; 10-Jan-2022 
SBT6050 
Silverback Therapeutics, Inc. – Confidential 
Page 105 of 105 
11.10 Document History 
Version 
Date 
Amendment 1 
10-Jan-2022 
Original 
30-Aug-2021