Conditions: Solid Tumor
Keywords: solid tumor HER2 mutation exon 20 insertion mutation HER2 positive Genes, HER2 Genes, erbb2 HER2 amplification HER2 overexpression genes, exon 20 insertion lung cancer non-small cell lung cancer breast cancer colon cancer colorectal cancer bladder cancer endometrial cancer gastric cancer biliary tract cancer
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 91
Healthy volunteers: no

Brief summary:
This was a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that had select mutations or alterations in human epidermal growth factor receptor 2 (HER2/ErbB2) genes or epidermal growth factor receptor (EGFR/ErbB1). The main goals of this study were to:

* Find the recommended dose of BDTX-189 that can be given safely to participants
* Learn more about the side effects of BDTX-189
* Learn what the body does to BDTX-189 after it has been taken (pharmacokinetics or PK)
* Determine the preliminary antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

Detailed description:
BDTX-189 is an irreversible, small molecular inhibitor that is highly selective versus wild-type EGFR and potent for cancer driver mutations of the ErbB family, including extracellular, transmembrane, and kinase domain allosteric mutations of HER2, as well as EGFR and HER2 exon 20 insertion mutations. These allosteric ErbB mutations are found in 1 - 2 % of most solid tumors and enriched in some cancers with a prevalence of about 2 - 7% such as in non-small cell lung cancer, breast cancer, colorectal cancer, bladder cancer, and endometrial cancer. Currently approved HER2 and EGFR directed therapies are not active against the spectrum of allosteric mutations at relevant and tolerated exposure levels.

This Phase 1/2 multi-center, open-label trial was a first-in-human study that evaluated BDTX-189 orally administered daily as a single agent in patients with solid tumors harboring select mutations or alterations. The Phase 1 portion was a dose escalation primarily designed to assess the safety and tolerability of BDTX-189 and to determine a recommended Phase 2 dose (RP2D). Phase 1 focused on patients with a solid tumor and with alterations such as:

* Allosteric HER2 or HER3 mutation(s)
* EGFR or HER2 exon 20 insertion mutation(s)
* HER2 amplified or overexpressing tumors
* EGFR exon 19 deletion or L858R mutation

Eligible mutations must have been determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory.

The Phase 2 portion was not initiated.

Arms:
arm 1: In Part A, cohorts of patients with select HER2, HER3, or EGFR alterations received increasing doses of BDTX-189.

Interventions: intervention 1: BDTX-189
Intervention descriptions: intervention 1: Participants received a daily, oral dose of BDTX-189 as part of a 3 week cycle.

Protocol document:
Prot_SAP_000.pdf: 
ClinicalTrials.gov Reference
NCT04209465
























 
 
Study Drug:  BDTX-189               Sponsor/Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
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Table 1 
BDTX-189-01 Schedule of Assessments Part A-Dose Escalation Including Food-Effect Cohorts 
Flow Chart (Part A Dose 
Escalation including food-
effect cohorts) 
Study period 
Screening 
Lead-in Phase 
Food Effect-Dose 
level 5 (400 mg 
QD) or higher 
Part A Dose Escalation BDTX-189 Treatment Period 
 
 
Study Proceduresa 
 
 
Cycle 1 
(±1 day for Days 8, 
15) 
Cycle 2 
(±2 days) 
Cycle 3, 4, 5 
and every 
other cycle 
thereafter (±2 
days) 
End of 
Treatment
c 
30-Day 
Safety 
Follow-
up Visitd 
Un- 
scheduled 
Visitse 
Study Day 
≤28 days 
prior to 
C1D1 
-4 
-1 
1b 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinu
e study 
drug 
30 days 
after last 
dose (±3) 
 
Informed consent 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examg 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Directed physical examg 
 
 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Weight 
X 
 
 
Xh 
 
 
 
 
 
X 
X 
X 
 
ECOG Performance Status 
X 
 
 
Xh 
 
 
X 
 
 
X 
X 
X 
X 
Vital signsi 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGj 
X 
 
 
Xk 
 
Xk 
X 
 
 
X 
X 
X 
X 
ECHO/MUGAl 
X 
 
 
 
 
 
 
 
 
Xl 
X 
 
X 
Hematology (CBC with 5-part 
differential and platelets)m 
X 
 
 
Xh,m 
X 
X 
X 
 
 
X 
X 
X 
X 
Clinical chemistrym,n 
X 
 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
Study Drug:  BDTX-189               Sponsor/Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
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Flow Chart (Part A Dose 
Escalation including food-
effect cohorts) 
Study period 
Screening 
Lead-in Phase 
Food Effect-Dose 
level 5 (400 mg 
QD) or higher 
Part A Dose Escalation BDTX-189 Treatment Period 
 
 
Study Proceduresa 
 
 
Cycle 1 
(±1 day for Days 8, 
15) 
Cycle 2 
(±2 days) 
Cycle 3, 4, 5 
and every 
other cycle 
thereafter (±2 
days) 
End of 
Treatment
c 
30-Day 
Safety 
Follow-
up Visitd 
Un- 
scheduled 
Visitse 
Study Day 
≤28 days 
prior to 
C1D1 
-4 
-1 
1b 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinu
e study 
drug 
30 days 
after last 
dose (±3) 
 
Coagulation (PT, aPTT, 
INR)h,m 
X 
 
 
Xh 
 
 
X 
 
 
X 
X 
 
 
Urinalysism,o 
X 
 
 
Xh 
 
 
X 
 
 
X 
X 
X 
X 
Pregnancy testp 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
PK sample collectionq 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
ctDNA sample collectionr 
 
 
 
X 
 
 
X 
 
 
Xr 
Xr 
 
 
Food administration for food 
effects 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
PK sample collection for food 
effectt 
 
X 
X 
 
 
X 
X 
 
 
X 
 
 
 
Archival tissue sampleu 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsyv 
 
 
 
Xv 
 
 
Xv 
 
 
 
Xv (optional) 
 
 
Tumor assessment (CT or 
MRI)w 
Xx 
 
 
Every 6 weeks (±3 days) from C1D1 for 1st 8 cycles and 
every 12 weeks (±7 days) thereafter 
X 
 
X 
Response assessment using 
RECIST v1.1x 
X 
 
 
Every 6 weeks (±3 days) from C1D1 for 1st 8 cycles and 
every 12 weeks (±7 days) thereafter 
X 
 
X 
Concomitant medications 
X 
 
 
**Collected from 14 days prior to C1D1 until 30-Day Safety Follow-up visit** 
X 


 
 
Study Drug:  BDTX-189               Sponsor/Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
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Flow Chart (Part A Dose 
Escalation including food-
effect cohorts) 
Study period 
Screening 
Lead-in Phase 
Food Effect-Dose 
level 5 (400 mg 
QD) or higher 
Part A Dose Escalation BDTX-189 Treatment Period 
 
 
Study Proceduresa 
 
 
Cycle 1 
(±1 day for Days 8, 
15) 
Cycle 2 
(±2 days) 
Cycle 3, 4, 5 
and every 
other cycle 
thereafter (±2 
days) 
End of 
Treatment
c 
30-Day 
Safety 
Follow-
up Visitd 
Un- 
scheduled 
Visitse 
Study Day 
≤28 days 
prior to 
C1D1 
-4 
-1 
1b 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinu
e study 
drug 
30 days 
after last 
dose (±3) 
 
Monitoring of AEs 
X 
 
 
**Collected from date when ICF is signed until 30 days after last dose of study drug** 
X 
Study drug dosing review 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; β-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; C = cycle; CBC = complete blood count; CT = computed tomography; ctDNA = 
circulating tumor deoxyribonucleic acid; D = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End-of-Treatment; 
ICF = informed consent form; INR = International Normalized Ratio; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; 
OS = overall survival; PFS = progression-free survival; PK = pharmacokinetic; PS = performance status; PT = prothrombin time; QD = once daily; QTc = QT interval corrected 
for heart rate; QTcF = QT interval corrected by Fridericia’s formula; RECIST = Response Evaluation Criteria for Solid Tumors; SRC = Safety Review Committee; WOCBP = 
women of child-bearing potential. 
a Perform all assessments prior to dosing unless otherwise specified.   
b The C1D1 visit will determine the visit calendar for the study, and all projected visits will be based on the C1D1 visit date.  Study visits must occur 
according to the study visit schedule and within the allowed protocol windows.  Missed doses or dose interruptions should not alter the patient’s study visit 
schedule. 
c Patients starting any new anti-cancer therapy after the last dose of study drug must complete the EOT visit assessments in advance of starting a new anti-cancer 
therapy. 
d All patients must complete the Safety Follow-up visit.  If the EOT visit is more than 30 days after the last dose of study treatment, the 30-Day Safety 
Follow-up visit is not required.  Patients starting any new anti-cancer therapy after the EOT visit must complete the 30-Day Safety Follow-up visit assessments 
in advance of starting the new anti-cancer therapy.  Thirty-Day Safety Follow-up visit assessments do not need to be repeated if the new anti-cancer therapy is 
initiated within 7 days of the EOT visit, unless further study drug was administered or there was a new abnormal test result when last assessed (including an 
abnormal test result which has worsened from previous).  Following the administration of any new anti-cancer therapy, patients will be followed until 30 days 
(±3 days) after the last dose of study drug for AEs and concomitant medications associated with these AEs only. 
e If additional visits are needed, these assessments may be obtained/performed/measured as clinically indicated. 


 
 
Study Drug:  BDTX-189               Sponsor/Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
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f Informed consent may be obtained during the 28-day window; however, the signed ICF must be obtained before any protocol-specific assessments are 
performed.  Tumor assessments (CT or MRI) and/or ECHO/MUGA may occur prior to signing of the ICF if completed at the clinical site as part of standard of 
care and performed in compliance with the protocol requirements. 
g A complete physical examination includes an exam of all body components; a directed physical examination is focused on a specific body part or disease, at 
the discretion of the Investigator.  The directed physical exam will include an ophthalmological exam if clinically indicated. 
h The following baseline assessments do not need to be reassessed at C1D1 if conducted within the prior 7 days and as part of the screening assessments: weight, 
ECOG PS, hematology (CBC with differential and platelets), clinical chemistry, coagulation, and urinalysis. 
i Vital sign measurements (heart rate, systolic and diastolic blood pressure, pulse oximetry, and oral or axillary temperature) will be performed prior to dosing of 
study drug. 
j Single ECGs are to be performed prior to dosing of study drug.  ECGs (single) will be obtained after the patient has been resting quietly in semi-supine 
position for at least 5 minutes before the ECG.  ECG parameters (PR interval, QRS interval, QT interval corrected for heart rate by Fridericia’s formula 
[QTcF], and heart rate) will be recorded.  When multiple assessments coincide, ECGs must be done immediately before the scheduled PK sample and/or any 
other blood draw. 
k Additional triplicate ECGs (time-matched to coincide with detailed PK assessments) beginning with dose level 4 (200 mg) and onwards will be obtained on 
C1D1 and C1D15 pre-dose and 1.0, 2.0, 3.0, and 4.0 hours (+/- 5 minutes) post-dose to evaluate QTc exposure effects.  For each time point, three standard 
resting 12-lead ECGs will be obtained in close succession and not more than 2 minutes apart (i.e., 4 minutes total for 3 ECGs).  ECGs will be obtained after the 
patient has been resting quietly in semi-supine position for at least 5 minutes before the first ECG and during the triplicate. 
l MUGA or ECHO should be performed at Screening (if not performed ≤6 weeks prior to patient signing informed consent), ≤7 days before dosing on C4D1, 
C7D1, C13D1, EOT, and as clinically indicated.  ECHO/MUGA may occur prior to signing of the ICF if completed at the clinical site as part of standard of 
care and performed in compliance with the protocol requirements. 
m Hematology will include CBC with hemoglobin, red blood cell count, total white blood cell count with ANC, absolute lymphocyte count, 5-part differential [% 
neutrophils, % lymphocytes, % or absolute value of: monocytes, basophils, eosinophils] and platelet count).  The Investigator (or designee) is responsible for 
reviewing available lab results for each patient prior to their first dose to ensure that there are no lab abnormalities or values worsening from screening that are 
clinically significant. 
n Clinical chemistry (±2 days) will include sodium, potassium, chloride, bicarbonate, BUN or blood urea, creatinine, glucose, bilirubin (total and direct), AST, 
ALT, LDH, alkaline phosphatase, amylase, lipase, calcium, magnesium, phosphorous, albumin, and total protein. 
o Urinalysis will include protein, glucose, ketones, urobilinogen, occult blood, and microscopic sediment evaluation.  A 24-hour urine collection for assessment 
of urine protein will be performed whenever the urinalysis reveals ≥3+ protein. 
p Negative serum ß-hCG pregnancy test within 7 days prior to the first dose of study drug will be required as an entry criterion for WOCBP.  For WOCBP, a 
urine sample or serum pregnancy test will be performed on Day 1 of Cycle 2-Cycle 5, then at each subsequent in-person visit while patient is on treatment 
(including the EOT visit). 
q See Section 5.6 and Table 10 for full PK profile and sparse PK sampling schemes.  On PK collection days, patients should be instructed to wait until they 
arrive at the study center and receive instructions from study staff prior to taking their dose of study medication.  Sparse PK will also be collected (sampling 
scheme: C2D1, C3D1, C4D1, C5D1 and every other cycle thereafter [± 2 days], 1 pre-dose sample and 2 post-dose blood draws: the 1st draw at 0.5-1.5 hours 
post-dose and the 2nd draw at 2-4 hours post-dose.)  Refer to Table 10.  Patients participating in the initial Dose Escalation where BDTX-189 was evaluated 
fasting should also take the study drug fasting for the detailed PK assessment.  Patients receiving BDTX-189 in the non-fasting state should be provided a meal 
of their choice in connection with the detailed PK assessment as instructed in Section 6.1.2. 
r ctDNA samples will be obtained pre-dose on C1D1, C2D1, C3D1, and at the EOT visit and/or time of disease progression for all patients enrolling onto Part 
A, including Food-Effect patients.  If not collected at the EOT visit, these samples may be collected at the 30-day Safety Follow-up visit as long as no new 
anticancer therapy has commenced.  (See Section 5.7.3) 


 
 
Study Drug:  BDTX-189               Sponsor/Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
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s After dose level 5 (400 mg QD) has been deemed tolerable by the SRC, or a later cohort has been deemed tolerable based on emerging data, Food Effect will 
be assessed during a lead-in phase for patients in that cohort.  On Day -4, patients will be randomized to receive BDTX-189 as a single oral dose after fasting 
for at least 10 hours before dosing or immediately after consuming breakfast.  Patients receiving the study drug in the fasted state will continue to fast for at 
least 4 hours after the dose.  Patients will receive BDTX-189 in the opposite prandial state on Day-1 (see Section 5.3.1). 
t Pharmacokinetic blood samples for the Food-Effect cohort will be taken at the time points listed in Table 11.  Full PK profiles will be collected on Day-4, 
Day 1, and C1D15.  Sparse PK will also be collected (sampling scheme: C2D1, C3D1, C4D1, C5D1 and every other cycle thereafter [± 2 days], 1 pre-dose 
sample and 2 post-dose blood draws: the 1st draw at 0.5-1.5 hours post-dose and the 2nd draw at 2-4 hours post-dose.)  Refer to Table 10.  On the days of PK 
collection, patients should be instructed to wait until they arrive at the study center and receive instructions from the research staff prior to taking their dose of 
study medication.  Patients participating in the initial Dose Escalation where BDTX-189 was evaluated fasting should also take the study drug fasting for the 
detailed PK assessment.  Patients receiving BDTX-189 in the non-fasting state should be provided a meal of their choice in connection with the detailed PK 
assessment as instructed in Section 6.1.2. 
u Archival tissue sample is only required for patients in Part A who have allosteric ErbB mutations and archival tissue available; tissue block is preferred.  For 
patients in the Safety Expansion portion of Part A, please see Table 2. 
v Patients in the Dose Escalation and Food-Effect portions of Part A will be required to undergo a fresh baseline and on-treatment tumor biopsy if the tumor is 
amenable for biopsy in the opinion of the Investigator.  The on-treatment biopsy will be obtained from dose level 5 (400 mg) and continue at higher dose levels 
until data supports target engagement in downstream signaling.  Fresh tumor biopsies will be collected at baseline (or within 28 days prior to C1D1), on C2D1 
(±5 days), and at the time of disease progression (the on-treatment tumor biopsy collected at disease progression will be optional for all patients who consent).  
On C2D1 (±5 days), patients must be dosed in the clinic at least 2 hours prior to collecting the biopsy.  The biopsy may be collected up to 8 hours after dosing.  
Depending on emerging data, C2D1 biopsies may be collected pre-dose (see Section 5.7.2). 
w Tumor assessment (CT or MRI of chest, abdomen, and pelvis, plus other sites of known disease at baseline) will be performed every 6 weeks (±3 days) for the 
first 8 cycles, then every 12 weeks (±7 days) thereafter, at EOT, and at the discretion of the Investigator.  Imaging should be completed within a window of -3 
days prior to D1 of odd cycles and should be reviewed before study drug administration on D1 for dosing determination.  Tumor assessment/imaging must be 
performed at the time of treatment discontinuation, unless it has been done within the past 4 weeks.  If disease progression according to RECIST (version 1.1) 
is documented at any time, no further tumor/response assessment will be required. 
x May be performed any time within 28 days prior to C1D1 and includes assessments completed at the clinical site as part of standard of care, and prior to the 
signing of the informed consent, if the assessments were performed in compliance with the protocol requirements.  Baseline assessment must include CT or 
MRI imaging of the chest and abdomen, through the level of the adrenals, and brain, if clinically indicated, as well as other sites of known disease.


 
 
Study Drug:  BDTX-189               Sponsor/Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
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Table 2  
BDTX-189-01 Schedule of Assessments Part A-Safety Expansion 
Flow Chart (Part A 
Safety Expansion) 
Study period 
Screening 
Part A Safety Expansion BDTX-189 
Treatment Period 
 
 
 
Study Proceduresa 
 
Cycle 1 
(±1 day for 
Days 8, 15) 
Cycle 2 
(±2 days) 
Cycle 3, 
4, 5 and 
every 
other 
cycle 
thereafter 
(±2 days)  
End of 
Treatmentc 
30-Day 
Safety 
Follow-
up 
Visitd 
Un- 
scheduled 
Visitse 
PFS/OSx 
Study Day 
≤28 days 
prior to 
C1D1 
1b 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinue 
study drug 
30 days 
after 
last dose 
(±3) 
 
 
Informed consent 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examg 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
Directed physical examg 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
Weight 
X 
Xh 
 
 
 
 
 
X 
X 
X 
 
 
ECOG Performance 
Status 
X 
Xh 
 
 
X 
 
 
X 
X 
X 
X 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECGj,k 
X 
Xk 
 
Xk 
X 
 
 
X 
X 
X 
X 
 
ECHO/MUGAl 
X 
 
 
 
 
 
 
Xl 
X 
 
X 
 


 
 
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Flow Chart (Part A 
Safety Expansion) 
Study period 
Screening 
Part A Safety Expansion BDTX-189 
Treatment Period 
 
 
 
Study Proceduresa 
 
Cycle 1 
(±1 day for 
Days 8, 15) 
Cycle 2 
(±2 days) 
Cycle 3, 
4, 5 and 
every 
other 
cycle 
thereafter 
(±2 days)  
End of 
Treatmentc 
30-Day 
Safety 
Follow-
up 
Visitd 
Un- 
scheduled 
Visitse 
PFS/OSx 
Study Day 
≤28 days 
prior to 
C1D1 
1b 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinue 
study drug 
30 days 
after 
last dose 
(±3) 
 
 
Hematology (CBC with 
5-part differential and 
platelets)m 
X 
Xh,m 
X 
X 
X 
 
 
X 
X 
X 
X 
 
Clinical chemistrym,n 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation (PT, aPTT, 
INR)m 
X 
Xh 
 
 
X 
 
 
X 
X 
 
 
 
Urinalysism,o 
X 
Xh 
 
 
X 
 
 
X 
X 
X 
X 
 
Pregnancy testp 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
PK sample collectionq 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
ctDNA sample 
collectionr 
 
X 
 
 
X 
 
 
Xr 
Xr 
 
 
 
Archival tissue sampleu 
X 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsy 
sample (optional)s 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor assessment (CT 
or MRI)t 
Xv 
Every 6 weeks (±3 days) from C1D1 for 1st 8 
cycles, every 12 weeks (±7 days) thereafter, 
and as part of PFS/OSx 
X 
 
X 
X 


 
 
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Flow Chart (Part A 
Safety Expansion) 
Study period 
Screening 
Part A Safety Expansion BDTX-189 
Treatment Period 
 
 
 
Study Proceduresa 
 
Cycle 1 
(±1 day for 
Days 8, 15) 
Cycle 2 
(±2 days) 
Cycle 3, 
4, 5 and 
every 
other 
cycle 
thereafter 
(±2 days)  
End of 
Treatmentc 
30-Day 
Safety 
Follow-
up 
Visitd 
Un- 
scheduled 
Visitse 
PFS/OSx 
Study Day 
≤28 days 
prior to 
C1D1 
1b 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinue 
study drug 
30 days 
after 
last dose 
(±3) 
 
 
Response assessment 
using RECIST v1.1v 
Xv 
Every 6 weeks (±3 days) from C1D1 for 1st 8 
cycles, every 12 weeks (±7 days) thereafter, 
and as part of PFS/OSx 
X 
 
X 
X 
Concomitant 
medications 
X 
**Collected from 14 days prior to C1D1 until 30-day Safety Follow-up 
visit, and as part of PFS/OSd,x** 
X 
X 
Monitoring of AEs 
X 
**Collected from date when ICF is signed through 30 days after the last 
dose of study drugd,x** 
X 
 
Study drug dosing 
revieww 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; β-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; C = cycle; CBC = complete blood count; CT = computed tomography; ctDNA = 
circulating tumor deoxyribonucleic acid; D = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End-of-
Treatment; ICF = informed consent form; INR = International Normalized Ratio; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated 
acquisition scan; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetic; PS = performance status; PT = prothrombin time; QTc = QT interval corrected 
for heart rate; QTcF = QT interval corrected by Fridericia’s formula; RECIST = Response Evaluation Criteria for Solid Tumors; WOCBP = women of child-bearing potential. 
a Perform all assessments prior to dosing unless otherwise specified.   
b The C1D1 visit will determine the visit calendar for the study, and all projected visits will be based on the C1D1 visit date.  Study visits must occur 
according to the study visit schedule and within the allowed protocol windows.  Missed doses or dose interruptions should not alter the patient’s study visit 
schedule. 
c Patients starting any new anti-cancer therapy after the last dose of study drug must complete the EOT visit assessments in advance of starting a new anti-cancer 
therapy. 


 
 
Study Drug:  BDTX-189               Sponsor/Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
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d All patients must complete the Safety Follow-up visit.  If the EOT visit is more than 30 days after the last dose of study treatment, the 30-Day Safety 
Follow-up visit is not required.  Patients starting any new anti-cancer therapy after the EOT visit must complete the 30-Day Safety Follow-up visit assessments 
in advance of starting the new anti-cancer therapy.  Thirty-Day Safety Follow-up visit assessments do not need to be repeated if the new anti-cancer therapy is 
initiated within 7 days of the EOT visit, unless further study drug was administered or there was a new abnormal test result when last assessed (including an 
abnormal test result which has worsened from previous).  Following the administration of any new anti-cancer therapy, patients will be followed until 30 days 
(±3 days) after the last dose of study drug for AEs and concomitant medications associated with these AEs only. 
e If additional visits are needed, these assessments may be obtained/performed/measured as clinically indicated. 
f Informed consent may be obtained during the 28-day window; however, the signed ICF must be obtained before any protocol-specific assessments are 
performed.  Tumor assessments (CT or MRI) and/or ECHO/MUGA may occur prior to signing of the ICF if completed at the clinical site as part of standard of 
care and performed in compliance with the protocol requirements. 
g A complete physical examination includes an exam of all body components; a directed physical examination is focused on a specific body part or disease, at 
the discretion of the Investigator.  The directed physical exam will include an ophthalmological exam if clinically indicated. 
h The following baseline assessments do not need to be reassessed at C1D1 if conducted within the prior 7 days and as part of the screening assessments: weight, 
ECOG PS, hematology (CBC with differential and platelets), clinical chemistry, coagulation, and urinalysis. 
i Vital sign measurements (heart rate, systolic and diastolic blood pressure, pulse oximetry, and oral or axillary temperature) will be performed prior to dosing of 
study drug. 
j Single ECGs are to be performed prior to dosing of study drug.  ECGs (single) will be obtained after the patient has been resting quietly in semi-supine 
position for at least 5 minutes before the ECG.  ECG parameters (PR interval, QRS interval, QT interval corrected for heart rate by Fridericia’s formula 
[QTcF], and heart rate) will be recorded.  When multiple assessments coincide, ECGs must be done immediately before the scheduled PK sample and/or any 
other blood draw. 
k Approximately 12-24 patients receiving the smaller and reformulated 200 mg tablet will have blood drawn at C1D1 and C1D15 to evaluate QTc exposure 
effects.  These patients will undergo additional triplicate ECGs (time-matched to coincide with detailed PK assessments) will be obtained at C1D1 and 
C1D15 pre-dose and 1.0, 2.0, 3.0, and 4.0 hours (+/- 5 minutes) post-dose to evaluate QTc exposure effects.  For each time point, three standard resting 12-lead 
ECGs will be obtained in close succession and not more than 2 minutes apart (i.e., 4 minutes total for 3 ECGs).  ECGs will be obtained after the patient has 
been resting quietly in semi-supine position for at least 5 minutes before the first ECG and during the triplicate.  On the PK collection day, patients should be 
instructed to wait until they arrive at the study center and receive instructions from study staff prior to taking their dose of study medication.  Refer to Section 
5.6 for further details.  
l MUGA or ECHO should be performed at Screening (if not performed ≤6 weeks prior to patient signing informed consent), ≤7 days before dosing on C4D1, 
C7D1, C13D1, EOT, and as clinically indicated.  ECHO/MUGA may occur prior to signing of the ICF if completed at the clinical site as part of standard of 
care and performed in compliance with the protocol requirements. 
m Hematology will include CBC with hemoglobin, red blood cell count, total white blood cell count with ANC, absolute lymphocyte count, and 5-part 
differential [% neutrophils, % lymphocytes, % or absolute value of: monocytes, basophils, eosinophils] and platelet count).  The Investigator (or designee) is 
responsible for reviewing available lab results for each patient prior to their first dose to ensure that there are no lab abnormalities or values worsening from 
screening that are clinically significant. 
n Clinical chemistry (±2 days) will include sodium, potassium, chloride, bicarbonate, BUN or blood urea, creatinine, glucose, bilirubin (total and direct), AST, 
ALT, LDH, alkaline phosphatase, amylase, lipase, calcium, magnesium, phosphorous, albumin, and total protein. 
o Urinalysis will include protein, glucose, ketones, urobilinogen, occult blood, and microscopic sediment evaluation.  A 24-hour urine collection for assessment 
of urine protein will be performed whenever the urinalysis reveals ≥3+ protein. 


 
 
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p Negative serum ß-hCG pregnancy test within 7 days prior to the first dose of study drug will be required as an entry criterion for WOCBP.  For WOCBP, a 
urine sample or serum pregnancy test will be performed on Day 1 of Cycle 2-Cycle 5, then at each subsequent in-person visit while patient is on treatment 
(including the EOT visit). 
q Approximately 12-24 selected patients in the Safety Expansion may initiate treatment with smaller reformulated 200 mg tablets.  These patients will undergo 
detailed PK evaluation at C1D1 and C1D15 as outlined in Table 10 and Section 5.6.  All patients enrolling onto the Safety Expansion will have blood drawn 
for sparse PK (sampling scheme: C2D1, C3D1, C4D1, C5D1 and every other cycle thereafter [± 2 days] 1 pre-dose sample and 2 post-dose blood draws: the 1st 
draw at 0.5-1.5 hours post-dose and the 2nd draw at 2-4 hours post-dose.)  On the PK collection day(s), patients should be instructed to wait until they arrive at 
the study center and receive instructions from study staff prior to taking their dose of study medication.   
r  ctDNA samples will be obtained pre-dose on C1D1, C2D1, C3D1, C5D1, and at the EOT visit and/or time of disease progression.  If not collected at the EOT 
visit, these samples may be collected at the 30-Day Safety Follow-up visit as long as no new anticancer therapy has commenced.  (See Section 5.7.3).   
s Fresh tumor biopsies will be optional; refer to Section 5.7.2 for collection details.   
t Tumor assessment (CT or MRI of chest, abdomen, and pelvis, plus other sites of known disease at baseline) will be performed every 6 weeks (from Cycle 1 
Day 1) for the first 8 cycles, then every 12 weeks thereafter, at EOT, and at the discretion of the Investigator.  Imaging should be completed within a window 
of -3 days prior to D1 of odd cycles and should be reviewed before study drug administration on D1 for dosing determination.  Tumor assessment/imaging 
must be performed at the time of treatment discontinuation, unless it has been done within the past 4 weeks.  If disease progression according to RECIST 
(version 1.1) is documented at any time, no further tumor/response assessment will be required. 
u Archival tissue sample is required for patients in the Safety Expansion who have allosteric ErbB mutations and archival tissue available; tissue block is 
preferred.  In the event that a tissue block is unavailable, 12-20 formalin-fixed paraffin-embedded unstained slides may be submitted.  If there is not enough 
archival tumor tissue, a new tumor tissue biopsy sample must be obtained during screening, prior to starting study treatment.  (See Section 5.7.1)  
v May be performed any time within 28 days prior to C1D1 and includes assessments completed at the clinical site as part of standard of care, and prior to the 
signing of the informed consent, if the assessments were performed in compliance with the protocol requirements.  Baseline assessment must include CT or 
MRI imaging of the chest and abdomen, through the level of the adrenals, and brain, if clinically indicated, as well as other sites of known disease. 
w A smaller and reformulated 200 mg tablet may be introduced and supplied to some patients during the Safety Expansion of Part A; these tablets will be 
available to all patients enrolling onto Part B.  Patients in Part A who initiated treatment with the larger-200 mg tablet may be switched to the smaller and 
reformulated 200 mg tablet at the beginning of their subsequent cycles. Detailed PK sampling will be collected on Day 15 (i.e., after 14 days of daily treatment 
with the smaller 200 mg tablet) of that subsequent cycle according to Table 8. 
x From the 30-Day Safety Follow-up visit, follow-up for OS, PFS, and first subsequent anti-cancer therapy, if available, will be obtained every 3 months 
(±14 days) until 2 years after the patient’s first dose of study drug, death, loss to follow-up, withdrawal of consent, or end of the whole trial.  Follow-up 
information about overall survival may be obtained by phone. 


 
 
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Table 3 
BDTX-189-01 Schedule of Assessments Part B 
Flow Chart (Part B) 
Study period 
Screening 
Part B BDTX-189 Treatment Period 
 
 
 
Study Proceduresa 
 
Cycle 1 
Cycle 2 
(±2 days) 
Cycle 3, 4, 5 and 
every other 
cycle thereafter 
(±2 days) 
End of 
Treatmentc 
30-Day 
Safety 
Follow-up 
Visitd 
Unscheduled 
Visitse 
PFS/OSu 
Study Day 
≤28 days 
prior to 
C1D1 
1b 
 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinue 
study drug 
30 days 
after last 
dose (±3) 
 
 
Informed consent 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examg 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
Directed physical examg 
 
 
 
 
 
 
 
 
 
X 
X 
 
Weight 
X 
Xh 
 
 
 
 
 
X 
X 
X 
 
 
ECOG Performance Status 
X 
Xh 
 
 
X 
 
 
X 
X 
X 
X 
 
Vital signsi 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
ePROw 
 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
12-lead ECGj 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
Xk 
X 
 
X 
 
Hematology (CBC with 5-part 
differential and platelets)l 
X 
Xh,l 
 
 
X 
 
 
X 
X 
X 
X 
 
Clinical chemistryl,m 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation (PT, aPTT, INR)l 
X 
Xh 
 
 
X 
 
 
X 
X 
 
 
 
Urinalysisl,n 
X 
Xh 
 
 
X 
 
 
X 
X 
X 
X 
 
Pregnancy testo 
X 
 
 
 
Xo 
 
 
Xo 
Xo 
 
X 
 


 
 
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Flow Chart (Part B) 
Study period 
Screening 
Part B BDTX-189 Treatment Period 
 
 
 
Study Proceduresa 
 
Cycle 1 
Cycle 2 
(±2 days) 
Cycle 3, 4, 5 and 
every other 
cycle thereafter 
(±2 days) 
End of 
Treatmentc 
30-Day 
Safety 
Follow-up 
Visitd 
Unscheduled 
Visitse 
PFS/OSu 
Study Day 
≤28 days 
prior to 
C1D1 
1b 
 
8 
15 
1 
8 
15 
1 
Within 3 
days of 
decision to 
discontinue 
study drug 
30 days 
after last 
dose (±3) 
 
 
PK samplesp 
 
X 
 
 
X 
 
 
X 
 
 
 
 
ctDNA sample collectionq 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
Archival/new tumor tissue 
samplev 
X 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsy (optional) 
 
 
 
 
 
 
 
 
Xr 
 
 
 
Tumor assessment (CT or 
MRI)s,u 
Xt 
Every 6 weeks (±3 days) from C1D1 for 1st 8 cycles, 
every 12 weeks (±7 days) thereafter, and as part of 
PFS/OSu 
X 
 
X 
X 
Response assessment using 
RECIST v1.1t 
X 
Every 6 weeks (±3 days) from C1D1 for 1st 8 cycles, 
every 12 weeks (±7 days) thereafter, and as part of 
PFS/OSu 
X 
 
X 
X 
Concomitant medicationsu 
X 
**Collected from 14 days prior to C1D1 until 30-Day Safety Follow-up visit and as 
part of PFS/OSu ** 
X 
X 
Monitoring of AEsu 
X 
**Collected from date when ICF is signed until 30 days after last dose of study drug 
** 
X 
 
Study drug dosing review 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; β-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; C = cycle; CBC = complete blood count; CT = computed tomography; ctDNA = 
circulating tumor deoxyribonucleic acid; D = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; ePRO= electronic patient 
reported outcomes; ICF = informed consent form; INR = International Normalized Ratio; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated 
acquisition scan; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetic; PS = performance status; PT = prothrombin time; QTc 
= QT interval corrected for heart rate; QTcF = QT interval corrected by Fridericia’s formula; RECIST = Response Evaluation Criteria for Solid Tumors; WOCBP = women of 
child-bearing potential. 


 
 
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a Perform all assessments prior to dosing unless otherwise specified. 
b The C1D1 visit will determine the visit calendar for the study, and all projected visits will be based on the C1D1 visit date.  Study visits must occur 
according to the study visit schedule and within the allowed protocol windows.  Missed doses or dose interruptions should not alter the patient’s study visit 
schedule. 
c Patients starting any new anti-cancer therapy after the last dose of study drug must complete the End of Treatment (EOT) visit assessments in advance of 
starting a new anti-cancer therapy. 
d Patients starting any new anti-cancer therapy after the EOT visit must complete the 30-Day Safety Follow-up visit assessments in advance of starting the new 
anti-cancer therapy.  Thirty-Day Safety Follow-up visit assessments do not need to be repeated if the new anti-cancer therapy is initiated within 7 days of the 
EOT visit, unless further study drug was administered or there was a new abnormal test result when last assessed (including an abnormal test result which has 
worsened from previous).  If the EOT visit is more than 30 days after the last dose of study treatment, the 30-Day Safety Follow-up visit is not required.  
Following the administration of any new anti-cancer therapy, patients will be followed until 30 days (±3 days) after the last dose of study drug for AEs and 
concomitant medications associated with these AEs only. 
e If additional visits are needed, these assessments may be obtained/performed/measured as clinically indicated. 
f Informed consent may be obtained during the 28-day window; however, the signed ICF must be obtained before any protocol-specific assessments are 
performed. 
g A complete physical examination includes an exam of all body components; a directed physical examination is focused on a specific body part or disease, at 
the discretion of the Investigator.  The directed physical exam will include an ophthalmological exam if clinically indicated. 
h The following baseline assessments do not need to be reassessed at C1D1 if conducted within the prior 7 days and as part of the screening assessments: weight, 
ECOG PS, hematology (CBC with differential and platelets), clinical chemistry, coagulation, and urinalysis. 
i Vital sign measurements will be performed prior to dosing. 
j Single ECGs are to be performed prior to dosing of study drug.  ECG parameters (PR interval, QRS interval, QT interval corrected for heart rate by Fridericia’s 
formula [QTcF], and HR) will be recorded.  Single ECGs will be performed unless triplicate is clinically indicated in the opinion of the Investigator (i.e., 
borderline QTc prolongation).  If a triplicate ECG is clinically indicated, three standard resting 12-lead ECGs will be obtained in close succession and not more 
than 2 minutes apart (i.e., 4 minutes total for 3 ECGs).  ECGs will be obtained after the patient has been resting quietly in semi-supine position for at least 
5 minutes before the first ECG and during the triplicate.  When multiple assessments coincide, ECGs must be done immediately before the scheduled PK 
sample and/or any other blood draw. 
k MUGA/ECHO should be performed at Screening (if not performed ≤6 weeks prior to patient signing informed consent), ≤7 days before dosing C4D1, C7D1, 
C13D1, EOT, and as clinically indicated.  ECHO/MUGA may occur prior to signing of ICF if completed at the clinical site as part of standard of care and 
performed in compliance with the protocol requirements (see Section 5.2). 
l Hematology will include CBC with hemoglobin, red blood cell count, total white blood cell count with ANC, absolute lymphocyte count, 5-part differential [% 
neutrophils, % lymphocytes, % or absolute value of: monocytes, basophils, eosinophils] and platelet count).  The Investigator (or designee) is responsible for 
reviewing available lab results for each patient prior to their first dose to ensure that there are no lab abnormalities or values worsening from screening that are 
clinically significant. 
m Clinical chemistry (±2 days) will include sodium, potassium, chloride, bicarbonate, BUN or blood urea, creatinine, glucose, bilirubin (total and direct), AST, 
ALT, LDH, alkaline phosphatase, amylase, lipase, calcium, magnesium, phosphorous, albumin, and total protein. 
n Urinalysis will include protein, glucose, ketones, urobilinogen, occult blood, and microscopic sediment evaluation.  A 24-hour urine collection for assessment 
of urine protein will be performed whenever the urinalysis reveals ≥3+ protein. 
o Negative serum ß-hCG pregnancy test within 7 days prior to the first dose of study drug will be required as an entry criterion for WOCBP.  A urine sample or 
serum pregnancy test will be performed on Day 1 of Cycle 2-Cycle 5, then at each subsequent in-person visit while patient is on treatment (including the EOT 
visit). 


 
 
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p On PK collection days, patients should be instructed to wait until they arrive at the study center and receive instructions from study staff prior to taking their 
dose of study medication.  Sparse PK will be collected (sampling scheme: C1D1, C2D1, C3D1, C4D1, C5D1 and every other cycle thereafter [± 2 days], 1 pre-
dose sample and 2 post-dose blood draws: the 1st draw at 0.5-1.5 hours post-dose and the 2nd draw at 2-4 hours post-dose.). 
q ctDNA samples will be obtained at Screening and pre-dose on C1D1, C2D1, C3D1, C5D1, C7D1, C9D1, subsequently every 4th cycle (C13D1, C17D1, 
C21D1, etc.), and at the EOT visit and/or time of disease progression.  If not collected at the EOT visit, these samples may be collected at the 30-day Safety 
Follow-up visit as long as no new anticancer therapy has commenced.  (See Section 5.7.3)  
r An optional on-treatment tumor biopsy will be collected at the time of disease progression for all patients who consent. 
s Tumor assessment (CT or MRI of chest, abdomen, and pelvis, plus other sites of known disease at baseline) will be performed every 6 weeks for the first 
8 cycles, and then every 12 weeks thereafter.  Imaging should be completed within a window of -3 days prior to D1 of odd cycles and should be reviewed 
before study drug administration on D1 for dosing determination.  Patients who discontinue treatment for reasons other than PD will undergo tumor assessment 
in accordance with the original schedule relative to C1D1.  Tumor assessment/imaging must be performed at the time of treatment discontinuation, unless it 
has been done within the past 4 weeks.  If disease progression according to RECIST (version 1.1) is documented at any time, no further tumor/response 
assessment will be required. 
t May be performed any time within 28 days prior to C1D1 and includes assessments completed at the clinical site as part of standard of care, and prior to the 
signing of the informed consent, if the assessments were performed in compliance with the protocol requirements.  Baseline assessment must include CT or 
MRI imaging of the chest and abdomen, through the level of the adrenals, and brain, if clinically indicated, as well as other sites of known disease. 
u From the 30-Day Safety Follow-up visit, follow-up for OS, PFS, and first subsequent anti-cancer therapy, if available, will be obtained every 3 months 
(±14 days) until 2 years after the first dose of study drug, death, loss to follow-up, withdrawal of consent, or end of the whole trial.  Follow-up information 
about overall survival may be obtained by phone. 
v Archival tissue sample is mandatory for patients in Part B who have archival tissue available; a tissue block is preferred.  In the event that a tissue block is 
unavailable, 12-20 formalin-fixed paraffin-embedded unstained slides may be submitted.  If there is not enough archival tumor tissue, a new tumor tissue 
biopsy sample must be obtained during screening, prior to starting study treatment.  (See Section 5.7.1).  
w ePROs collection will occur C1D1, C1D8 and on Day 1 of every cycle from C2-C9.  After C9D1 collection will occur every 3 months (±14 days), at the EOT 
visit, and 30-Day Safety Follow-up visit.  Continue to collect ePROs even if the patient has discontinued taking the study drug until subsequent anti-tumor 
therapy is initiated.  Please note ePROs should be provided to the patient as soon as they arrive at the site for their visit, ideally before any other assessments 
are performed.  Refer to Section 5.3.4. 


 
 
 
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LIST OF ABBREVIATIONS
Abbreviation or special 
term 
Explanation 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the plasma concentration-time curve 
BCRP 
Breast cancer resistant protein 
BDTX 
Black Diamond Therapeutics 
BICR 
Blinded independent central review 
BID 
Twice daily 
BOIN 
Bayesian optimal interval 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid 
DCR 
Disease control rate 
Development Innovations 
Sarah Cannon Development Innovations 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capturing system 
EGFR 
Epidermal growth factor receptor 
EOT 
End-of-Treatment 
ePRO 
Electronic patient reported outcome 
EQ-5D 
EuroQol Group’s 5-domain 5-level questionnaire 
FA 
Full analysis  
FACT 
Functional Assessment of Cancer Therapy 


 
 
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Abbreviation or special 
term 
Explanation 
FACT-G 
Functional Assessment of Cancer Therapy-General 
FBSI 
Functional Assessment of Cancer Therapy Breast Symptom Index 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FLSI 
Functional Assessment of Cancer Therapy Lung Cancer Symptom Index 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HER2 
Human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
IB 
Investigator’s Brochure 
IC50 
Half-maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Study File 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MRI 
Magnetic resonance imaging 
MTC 
Mutational cluster 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute  
NE 
Non-evaluable 
NGS 
Next-generation sequencing 
NSCLC 
Non-small cell lung cancer 
NTL 
Non-target lesion 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PDx 
Pharmacodynamic 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 


 
 
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Abbreviation or special 
term 
Explanation 
PHI 
Protected health information 
PK 
Pharmacokinetic 
PO 
Orally/by mouth 
PopPK 
Population pharmacokinetics 
PR 
Partial response 
PRO 
Patient reported outcome 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PT 
Prothrombin time 
QD 
Once daily 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T wave 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
R to R interval 
ECG interval measured between two R waves of the QRS signal 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected adverse reaction 
SCRI 
Sarah Cannon Research Institute 
SD 
Stable disease 
SRC 
Safety Review Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Median elimination half-life 
TEAE 
Treatment-emergent adverse event 
TGI 
Tumor growth inhibition 
TKI 
Tyrosine-kinase inhibitor 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of child-bearing potential 
WT 
Wild type 


 
 
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TABLE OF CONTENTS 
BDTX-189-01 PROTOCOL SYNOPSIS ................................................................................ 6 
LIST OF ABBREVIATIONS ................................................................................................ 27 
TABLE OF CONTENTS ....................................................................................................... 30 
1. 
INTRODUCTION ................................................................................................. 35 
1.1 
Background ........................................................................................................... 35 
1.1.1. 
Allosteric ErbB Oncogenic Mutations: Clustering at the Structural Hotspots ...... 37 
1.1.2. 
Approved Therapies for Patients with Allosteric ErbB Oncogenic Mutations ..... 39 
1.1.3. 
Investigational Therapies for Patients with Allosteric ErbB Oncogenic 
Mutations ............................................................................................................... 41 
1.1.4. 
BDTX-189 ............................................................................................................. 41 
1.1.5. 
Non-clinical Experience ........................................................................................ 42 
1.1.6. 
Toxicology............................................................................................................. 46 
1.1.7. 
Clinical Experience ............................................................................................... 47 
1.1.8. 
Study Rationale and Rationale for Starting Dose .................................................. 48 
1.2. 
Potential Risks and Benefits of the Treatment Regimen ....................................... 49 
1.2.1. 
Precautions and Risks Associated with BDTX-189 .............................................. 51 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 52 
2.1. 
Primary Objective.................................................................................................. 52 
2.2. 
Secondary Objectives ............................................................................................ 52 
2.3. 
Exploratory Objectives .......................................................................................... 52 
2.4. 
Endpoints ............................................................................................................... 53 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 55 
3.1. 
Inclusion Criteria ................................................................................................... 55 
3.2. 
Exclusion Criteria .................................................................................................. 57 
3.3. 
Discontinuation from Study Treatment ................................................................. 59 
4. 
STUDY DESIGN .................................................................................................. 61 
4.1. 
Part A (Phase 1 - Dose Escalation and Safety Expansion) .................................... 61 
4.2. 
Part B (Phase 2) ..................................................................................................... 62 
4.3. 
Treatment Plan ...................................................................................................... 64 
4.3.1. 
Dose-Escalation Procedure.................................................................................... 65 
4.3.2. 
Dose-limiting Toxicity .......................................................................................... 67 
4.3.3. 
Maximum-tolerated Dose ...................................................................................... 68 
4.3.4. 
Safety Expansion after Determination of the Maximum-Tolerated Dose ............. 68 
4.3.5. 
Dose Modifications ............................................................................................... 69 
4.4. 
Treatment Duration ............................................................................................... 72 
4.5. 
Concomitant Medications...................................................................................... 73 


 
 
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4.5.1. 
Permitted Concomitant Medications ..................................................................... 73 
4.5.2. 
Prohibited Concomitant Medications .................................................................... 74 
4.5.3. 
Concomitant Medications to be Used with Caution .............................................. 75 
5. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 76 
5.1. 
Overview ............................................................................................................... 76 
5.2. 
Screening ............................................................................................................... 76 
5.3. 
Assessments During Study Treatment .................................................................. 78 
5.3.1. 
Food-effect Assessment (Dose Escalation Part A)................................................ 78 
5.3.2. 
Electrocardiogram Measurements ......................................................................... 79 
5.3.3. 
Response Assessments .......................................................................................... 79 
5.3.4. 
Patient Reported Outcomes (Part B only) ............................................................. 80 
5.4. 
Follow-up Periods and Study Completion ............................................................ 80 
5.4.1. 
End-of-Treatment Visit ......................................................................................... 80 
5.4.2. 
30-day Safety Follow-up Visit .............................................................................. 80 
5.4.3. 
Extended Follow-up Period (Safety Expansion and Part B) ................................. 81 
5.5. 
Early Patient Termination/Patient Withdrawal ..................................................... 81 
5.6. 
Pharmacokinetic Assessments ............................................................................... 81 
5.6.1. 
Pharmacokinetic Assessments – Food Effect (Part A) .......................................... 83 
5.7. 
Biomarker Assessments ........................................................................................ 84 
5.7.1. 
Archival Tumor Samples....................................................................................... 84 
5.7.2. 
Fresh Biopsies ....................................................................................................... 84 
5.7.3. 
Blood Samples for Circulating Tumor DNA (ctDNA)Analysis ........................... 85 
6. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
RISK INFORMATION ......................................................................................... 87 
6.1. 
BDTX-189 ............................................................................................................. 87 
6.1.1. 
Labeling, Packaging, and Supply .......................................................................... 87 
6.1.2. 
Preparation and Administration of BDTX-189 ..................................................... 87 
6.1.3. 
Accountability for All Study Drugs ...................................................................... 88 
7. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 89 
8. 
SAFETY REPORTING AND EVALUATION .................................................... 90 
8.1. 
Definitions ............................................................................................................. 90 
8.1.1. 
Adverse Events ...................................................................................................... 90 
8.1.2. 
Serious Adverse Events ......................................................................................... 90 
8.1.3. 
Adverse Event Severity ......................................................................................... 91 
8.1.4. 
Suspected Adverse Reaction ................................................................................. 91 
8.1.5. 
Recording and Reporting of Adverse Events ........................................................ 91 
8.1.6. 
Assessment of Adverse Events.............................................................................. 92 
8.2. 
Serious Adverse Event Reporting by the Investigator .......................................... 92 
8.2.1. 
Diagnosis versus Signs and Symptoms ................................................................. 93 
8.2.2. 
Persistent or Recurrent Adverse Events ................................................................ 93 


 
 
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8.2.3. 
Abnormal Laboratory or Vital Sign Values .......................................................... 94 
8.2.4. 
Hy’s Law ............................................................................................................... 94 
8.2.5. 
Deaths .................................................................................................................... 94 
8.2.6. 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 95 
8.2.7. 
Pre-Existing Medical Conditions .......................................................................... 95 
8.2.8. 
New Cancers.......................................................................................................... 95 
8.2.9. 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 96 
8.2.10. 
BDTX-189 Overdose ............................................................................................ 96 
8.3. 
Sponsor Serious Adverse Event Reporting Requirements .................................... 96 
8.3.1. 
Sponsor Assessment of Expectedness ................................................................... 96 
9. 
STATISTICAL CONSIDERATIONS .................................................................. 98 
9.1. 
Statistical Design ................................................................................................... 98 
9.2. 
Estimands .............................................................................................................. 98 
9.3. 
Sample Size Considerations .................................................................................. 99 
9.3.1. 
Phase 1 (Part A) ..................................................................................................... 99 
9.3.2. 
Phase 2 (Part B) ..................................................................................................... 99 
9.4. 
Analysis Population ............................................................................................. 101 
9.5. 
Data Analysis ...................................................................................................... 102 
9.5.1. 
Demographics and Baseline Characteristics ....................................................... 102 
9.5.2. 
Hypotheses to be Tested ...................................................................................... 102 
9.5.3. 
Efficacy Analysis ................................................................................................ 102 
9.5.4. 
Sub-group Analyses ............................................................................................ 103 
9.5.5. 
Safety Analysis .................................................................................................... 104 
9.5.6. 
Pharmacokinetics................................................................................................. 104 
9.5.7. 
Biomarkers .......................................................................................................... 105 
9.5.8. 
Quality of Life ..................................................................................................... 105 
9.6. 
Analysis Time Points........................................................................................... 105 
9.6.1. 
Final Analysis ...................................................................................................... 105 
9.6.2. 
Planned Interim Analysis .................................................................................... 105 
10. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................. 106 
10.1. 
Monitoring ........................................................................................................... 106 
10.2. 
Audits and Inspections ........................................................................................ 106 
10.3. 
Study Committees ............................................................................................... 106 
10.3.1. 
Safety Review Committee (Part A Only) ............................................................ 106 
10.3.2. 
Data Monitoring Committee (Part B Only) ......................................................... 107 
10.3.3. 
Blinded Independent Central Review Committee ............................................... 107 
10.3.4. 
Protocol Steering Committee .............................................................................. 107 
11. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS .......... 108 
11.1. 
Institutional Review Board Approval.................................................................. 108 
11.2. 
Regulatory Approval ........................................................................................... 108 


 
 
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11.3. 
Study Registration ............................................................................................... 108 
11.4. 
Informed Consent ................................................................................................ 109 
11.4.1. 
Confidentiality ..................................................................................................... 109 
11.5. 
Financial Information .......................................................................................... 110 
12. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ...... 111 
12.1. 
Amendments to the Protocol ............................................................................... 111 
12.2. 
Documentation Required to Initiate the Study .................................................... 111 
12.3. 
Study Documentation and Storage ...................................................................... 112 
12.4. 
Data Collection .................................................................................................... 113 
12.5. 
Disclosure and Publication Policy ....................................................................... 114 
REFERENCES .................................................................................................................... 115 
 
LIST OF TABLES 
Table 1 
BDTX-189-01 Schedule of Assessments Part A-Dose Escalation 
Including Food-Effect Cohorts ................................................................ 13 
Table 2  
BDTX-189-01 Schedule of Assessments Part A-Safety Expansion ........ 18 
Table 3 
BDTX-189-01 Schedule of Assessments Part B ..................................... 23 
Table 4 
Study Objectives and Corresponding Endpoints ..................................... 53 
Table 5 
Dose Levels Projected for Evaluation (Part A) ........................................ 65 
Table 6 
Dose Escalation/De-escalation Rules for Bayesian Optimal Interval 
Design Once Daily Dosing ...................................................................... 66 
Table 7 
Dose Reduction Levels for BDTX-189 Administered Once or Twice 
Daily ......................................................................................................... 69 
Table 8 
Dose Modification Guidelines for BDTX-189-related Adverse 
Events ....................................................................................................... 70 
Table 9 
ePRO Assessments (Part B only) ............................................................. 80 
Table 10 
BDTX-189 pharmacokinetic collection times (Part A Dose 
Escalation and Safety Expansion patients) .............................................. 82 
Table 11 
BDTX-189 pharmacokinetic collection times – Lead-in phase for 
Food-Effect (Part A) ................................................................................ 83 
Table 12 
Operating Characteristics for Cohorts 1 and 2 ....................................... 100 
Table 13 
Operating Characteristics for Cohort 3 .................................................. 100 
Table 14 
Operating Characteristics for Cohort 4 .................................................. 101 
Table 15 
Operating Characteristics for Cohort 5 .................................................. 101 








 
 
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potentially actionable alterations with improved sensitivity and reduced tissue requirements 
compared to serial polymerase chain reaction (PCR) or immunohistochemistry (IHC).  Tumor 
tissue may not always be available for testing by NGS due to lack of adequate material or 
because it is not possible to obtain new biopsy material.  Moreover, tumor tissue may not reflect 
the intratumoral heterogeneity which could result in false negative test results.  Liquid biopsies 
are a less burdensome approach which is becoming more commonly used for circulating tumor 
deoxyribonucleic acid (ctDNA) analysis by NGS to identify genomic alterations and for 
longitudinal monitoring of disease response and early relapse (Neumann et al. 2018).  Although 
not all detected alterations represent actionable molecular targets, molecular testing has become 
standard in some disease settings such as NSCLC, because driver mutations are identified in up 
to 55% of lung adenocarcinoma (Hirsch et al. 2017).  Since the Food and Drug Administration 
(FDA) approval of pembrolizumab, larotrectinib, and entrectinib for tumor agnostic indications, 
patients with a wide range of solid malignancies are now candidates for sequencing by NGS.  
However, these diagnostic tests have outpaced the development of precision therapies.  The 
majority of patients diagnosed today have tumors with genetic profiles for which there are no 
targeted therapies. 
1.1.1. 
Allosteric ErbB Oncogenic Mutations: Clustering at the Structural Hotspots 
BDTX-189 also targets groups of mutations expressed at lower frequency, termed tail mutations.  
The clusters of mutations (MTCs) targeted by BDTX-189 comprise both anchor and tail 
mutations (refer to Figure 3).  
Figure 3 
Anchor (red) and Tail (blue) 
 Mutations Expressed in Human Tumors 
 
Abbreviations: 
; MTC = mutational cluster. 
The anchor and tail driver mutations are often found aggregated within several functionally 
critical regions of 
.  For MTC-A, which comprises the 
 mutation, 
the most common insertions of ASV, SVD, NPH, and FQEA account for 40-50% while the 
remaining are much less frequent (Oxnard et al. 2013, Arcila et al. 2013).  Black Diamond 
Therapeutics, Inc. (BDTX) has used this structural and functional information to group the 
family of allosteric oncogenic 
 mutations into MTCs, which will enable their clinical 
assessment in the BDTX-189-01 study.  The clustering scheme of validated oncogenic 
 
mutations is based on three criteria relating to protein structure and dynamics: 
1) mutations that occur in close proximity within the 3-dimensional protein conformation 
2) mutations that occur in common dynamic domains of the target protein, and 
3) mutations that relate to similar local conformational changes in protein structure. 
Grouping these allosteric 
oncogenic mutations into clusters for clinical evaluation allows 
BDTX to test for differences in response rates between groups of targeted mutations that may 








 
 
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1.1.3. 
Investigational Therapies for Patients with Allosteric ErbB Oncogenic Mutations 
The most recent meta-analysis of 3,920 records (including 5 clinical and 32 real-world evidence 
studies) suggest that the outcome of treatments in patients with NSCLC harboring 
 
 mutations with currently approved TKIs and immune-oncology agents remains poor 
to sub-optimal (Tomaras et al. 2020).  However, several investigational agents such as 
 
and 
 directed TKIs and mAbs are being evaluated in clinical studies.  Mobocertinib/TAK-
788 is a small molecule TKI that has demonstrated activity in NSCLC patients with 
 
mutations with an ORR of 43% (12/28 patients) and median PFS of 7.3 months in a 
Phase 1/2 trial (Riely et al. 2020).  Preliminary data from a single-center study for poziotinib, 
another small molecule TKI, showed an ORR of 58% at week 8 and median PFS of 5.6 months 
in NSCLC patients with 
 mutations (Heymach et al. 2018).  However, data from 
the larger multi-center Phase 2 ZENITH20 study in 115 NSCLC patients with 
 
 mutations showed poorer results, with ORR of 15% and a median PFS of 4.2 months 
(Le et al. 2020).  Amivantamab, a bispecific anti-
 and anti-
 antibody, showed activity 
in NSCLC patients with 
 mutations with an ORR of 28% (14/50 
patients) and median PFS of 8.3 months (Park et al. 2020).  The safety of mobocertinib and 
poziotinib has been characterized by toxicities, including typical 
 events such as 
diarrhea (Grade 3 or higher in 32% of patients treated with mobocertinib, and in 26% of patients 
treated with poziotinib), and skin rash (Grade 3 or higher in 1% of patients for mobocertinib, and 
in 28% for poziotinib).  Amivantamab had Grade 3 or higher events in 36% of patients, with 1 
Grade 3 diarrhea event. 
In NSCLC patients harboring 
 mutations, poziotinib has shown an ORR 
of 28% and PFS of 5.5 months in the Phase 2 ZENITH20 study (Socinski et al. 2020).  Interim 
results from the DESTINY trial have shown that trastuzumab deruxtecan/DS-8201, an antibody 
drug conjugate, had an ORR of 62% (26/42 patients) and median PFS of 14.0 months in NSCLC 
patients harboring 
 mutations predominantly in the kinase domain (Smit et al. 2020).  But 
as with poziotinib, trastuzumab deruxtecan/DS8201 also had high levels of toxicity, with 64% 
Grade 3 or higher events and 38% of patients with dose reductions. 
There is a critical unmet medical need for precision treatment of patients with locally advanced 
or metastatic solid tumors harboring an allosteric ErbB mutation domain. 
1.1.4. 
BDTX-189 
BDTX-189 is an orally available, highly potent and selective irreversible inhibitor of ErbB 
allosteric mutations and kinase domain active site mutations.  These mutations are constitutively 
activated, ligand-independent receptors that are resistant to currently approved 
 or 
 
TKIs or mAbs at therapeutically relevant and tolerable systemic exposure levels.  BDTX-189 
binds covalently to the ATP-binding site of the mutant receptor at very low concentrations.  The 
drug has been designed to minimize or eliminate the typical dose-limiting AEs such as rash and 
diarrhea associated with 
 TKIs by sparing 
 receptors. 
BDTX-189 exhibits in vitro activity against the most commonly occurring ErbB family 
mutations (please see the Investigator’s Brochure [IB]). 
Preclinical pharmacology studies have also demonstrated relevant activity of BDTX-189 against 
targets that results in oncogenic transformation other than allosteric ErbB mutations.  These 










 
 
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• Reduced solubility of BDTX-189 at increasing pH may result in decreased exposures 
with concomitant use of acid-reducing agents and food 
• Plasma protein unbound fraction: 1.5% 
• Metabolized mainly by CYP3A4, with multiple alternative pathways and glutathione 
conjugation; no CYP-mediated perpetrator drug interactions expected.  However, the use 
of strong CYP3A inhibitors and inducers with BDTX-189 is prohibited. 
• BDTX-189 is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP) and coadministration with strong inhibitors of P-gp or BCRP should be used 
with caution.  BDTX-189 is a moderate inhibitor of BCRP and sensitive substrates should 
be used with caution. 
• Negligible excretion in urine as parent 
1.1.6. 
Toxicology 
The rat and dog were chosen as appropriate toxicology species based on the comparative 
metabolic profiling of BDTX-189 in the liver microsomes and hepatocytes of rats, dogs, and 
humans. 
In the definitive good laboratory practice (GLP) study, following oral administration of 
BDTX - 189 QD over a period of 28 days to male and female rats, the highest non-severely toxic 
dose (HNSTD) was 30 mg/kg/day.  This was based on BDTX-189-related clinical signs observed 
at 60 mg/kg/day in females, including body weight loss, piloerection, hunched posture, and 
reduced food intake.  Males tolerated daily administration of 60 mg/kg/day for the full 28-day 
dosing period, but food intake was slightly lowered during the first week of treatment and the 
overall body weight gain was 27% less than that of concurrent controls.  There were no BDTX-
189-related clinical signs at 10 or 30 mg/kg/day.  There were no effects on urinalysis and organ 
weights, nor were there ocular changes or effects on functional/behavioral observation 
parameters at any dose level.  Microscopic changes considered related to treatment consisted of 
slight and reversible inflammation and hyperplasia of the mucosa in various regions of the 
gastrointestinal tract at all dose levels, and at the mid- and high dose levels were accompanied by 
elevated total white blood cell (WBC) counts (primarily neutrophils).  Following a 14-day 
recovery period, inflammation in the gastrointestinal tract and WBC counts were completely 
reversed. 
In the definitive GLP study, following oral administration of BDTX-189 BID over a period of 28 
days to male and female dogs, the 20 mg/kg BID dose level (40 mg/kg/day) was poorly tolerated, 
with marked clinical signs, inappetence, and weight loss necessitating the premature termination 
of one animal on Day 17.  Dose levels of 10 and 20 mg/kg/day were well tolerated.  Based on in-
life and pathology findings, the HNSTD was 20 mg/kg/day (10 mg/kg BID).  Microscopic 
findings were consistent with a primary irritant effect to the proximal gastrointestinal tract, with 
associated secondary changes within the mesenteric lymph node and pancreas.  Secondary 
changes noted in mesenteric lymph node consisted of increased sinus erythrocytes, a reaction to 
the gastrointestinal effect, and was not noted in other peripheral lymph nodes.  In the pancreas, 
only edema was noted without any evidence of degeneration or inflammation.  Slight 
inflammation of the renal papilla in one animal administered 40 mg/kg/day was of uncertain 


 
 
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pathogenesis and its relationship to BDTX-189 is uncertain.  Complete or partial reversibility 
was demonstrated following the 14-day treatment-free period, with the exception of the duodenal 
glandular dilatation, which would be expected to resolve over a longer recovery period. 
BDTX-189 did not show effects on cardiovascular or respiratory function in GLP safety 
pharmacology studies in dog and rat, respectively.  BDTX-189 was not an inhibitor of human 
ether-à-go-go related gene (hERG) at concentrations up to and including 7.5 µM.  BDTX-189 
did not show evidence of phototoxic potential in vitro.  BDTX-189 did not show evidence of 
mutagenicity or clastogenicity in in vitro GLP genotoxicity assays. 
1.1.7. 
Clinical Experience 
As of 02 April 2021, preliminary safety data were available for 65 patients from Part A of this 
study who have received at least 1 dose of BDTX-189, including 55 patients who were 
administered a QD schedule with doses including 25 to 200 mg (n=5, fasting), 400 mg (n=7, 
fasting), 800 mg (n=21, fasting), 800 mg (n=9, non-fasting [NF]), 1000 mg (n=7, NF), 1200 mg 
(n=6, fasting). A total of 10 patients have received the BID schedule, with doses of 600 mg (n=5, 
NF) and 800 mg (n=5, NF).   
The DLT-evaluable population consisted of 45 patients who were enrolled into the dose-
escalation cohorts.  No DLTs have been reported with doses of 800 mg BDTX-189 QD (fasting 
or NF) or less in the dose escalation cohorts.  The MTD was exceeded with 2 patients in each of 
the cohorts receiving either 1200 mg QD (fasting) or 1000 mg QD (NF).  The 800 mg QD, NF 
dose was considered the MTD and the recommended phase 2 dose (RP2D). The 800 mg and 
600 mg BID fasting doses also exceeded the MTD with 3 patients each experiencing DLTs.  A 
cohort evaluating 400 mg BID, NF is currently enrolling.   
The majority of DLTs were gastrointestinal in nature with diarrhea reported in 6 patients, 
vomiting in 5, and nausea in 4. Other DLTs reported by 1 patient included increased alanine 
aminotransferase (ALT) with or without increased aspartate aminotransferase (AST), increased 
bilirubin, increased creatinine, and dehydration. Some patients experienced more than 1 DLT, 
and these were either Grade 2 or 3 severity.  
The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea 
(58.5%), nausea (47.7%), vomiting (44.6%), fatigue (29.2%), and increased ALT (23.1%).  No 
dose relationship was observed in TEAEs reported. The majority of the TEAEs were Grade 1 or 
2 (mild or moderate) with 43.1% of patients reporting TEAEs of Grade ≥3.  The most frequently 
reported TEAEs Grade ≥3 included diarrhea (15.4%) and increased ALT (7.7%); all were 
considered by the Investigator to be related to the study treatment.  
Preliminary PK data available for 43 patients showed oral absorption was generally rapid.  In the 
multiple patient cohorts, there were dose-dependent increases in exposure (i.e., maximum 
concentration [Cmax] and area under the plasma concentration-time curve [AUC]) seen with 
single (C1D1) and multiple (C1D15) daily administrations) up to 800 mg, before an exposure 
plateau was reached at 1200 mg (see Figure 8).  Exposures at 800 mg QD were approximately 
1.5-fold lower than projected from preclinical data.  The median elimination half-life (t1/2) across 
all dose levels ranged from 2.2 to 5.9 hours, which is in line with preclinical projections of 
approximately 2 hours.  No consistent trend of accumulation or decreasing exposures on multiple 
dosing was indicated. In the ongoing Food Effect cohorts, evaluating the effect of a high-fat or 


 
 
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low-fat meal on the PK of BDTX-189, 6 patients are considered evaluable in each cohort.  The 
effect of a high-fat meal on the PK of BDTX-189 suggests a slightly positive effect of food with 
geometric mean ratio for Cmax and AUC0-t of 1.0 and 2.3 respectively. Administration of BDTX-
189 with food resulted in an approximately 2.5-fold increase in median tmax (median tmax 1.5 
hours fasted, 3.5 hours low-fat meal, 4.0 hours high-fat meal) relative to administration in the 
fasted state, and no change in median t1/2. 
Based on the results described above, the Safety Review Committee (SRC) recommended that 
the remaining patients to be enrolled will be administered BDTX-189 following consumption of 
a meal (i.e., NF). 
Figure 8 
Relationship Between BDTX-189 Dose (mg/day QD) and Exposure (C1D1 
Cmax and AUC0-t) 
 
AUC0-t=area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration; 
Cmax=maximum concentration. 
1.1.8. 
Study Rationale and Rationale for Starting Dose 
Allosteric mutations in 
 and 
 have been identified and characterized; these mutations 
encode molecular changes in these oncogenic targets that are not located at traditional substrate 
or inhibitor binding sites, but rather act at a distance to influence the binding properties of these 
sites.  BDTX-189 is highly potent against these allosteric mutations which are found in 1% to 
2% of a large variety of solid tumors but are enriched in tumors such as advanced NSCLC, 
invasive breast cancer, bladder cancer, and endometrial cancer.  Currently available 
 and 
 TKIs or mAbs have limited or no antitumor activity against these genetic alterations either 
because of insufficient potency or lack of selectivity which results in toxicity before adequate 
exposures are achieved.  Therefore, there is a high unmet medical need for a large group of 
patients currently not served.  The goal of the development plan for BDTX-189 is to efficiently 
evaluate the antitumor activity across a broad range of solid tumor types expressing allosteric 
ErbB mutations. 
BDTX-189 binds covalently to the ATP-binding site of the mutant receptor at very low 
concentrations (IC50 < 77 nM cellular potency).  It has been demonstrated that BDTX-189 
remains bound to mutant receptors for at least 24 hours, with site occupancy >50% at 24 hours 
after probe addition.  This observation has been confirmed in vivo, where oral administration of 
BDTX-189 to athymic nude mice bearing allosteric ErbB mutant BaF3 allografts showed 
suppression of target phosphorylation for at least 24 hours.  This indicates that BDTX-189 binds 


 
 
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to the active site of ErbB allosteric mutants via a slow off-rate or covalent mechanism supporting 
once daily dosing in humans. 
The determination of the Phase 1 starting dose in cancer patients was based on the results of the 
28-day GLP toxicology studies in rat and dog.  The human equivalent dose at the HNSTD in rat 
and dog is 180 mg/m2 and 400 mg/m2, respectively, and as such defined rat as the most sensitive 
species.  The proposed maximum recommended starting dose was calculated in accordance with 
the International Council for Harmonisation (ICH) S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals (adopted by the FDA, 2010) using the toxic dose in 10% of animals (STD10), 
which in rat was exceeded at 60 mg/kg/day and a dose of 30 mg/kg/day was the HNSTD.  The 
starting dose was calculated as 25 mg QD as follows: 30 mg/kg/day (highest dose level < STD10 
in rat) × 6 (human equivalent dose mg/m2 conversion) × 1/10 (rodent safety factor) × 1.62 
(human body surface area), and rounded down to the nearest multiple of 5. 
With a starting dose of 25 mg QD and the projected dose to achieve exposures associated with 
antitumor activity in humans being 400 to 800 mg QD (see Section 1.1.5.2), this justifies using 
single-patient cohorts during the accelerated titration with doubling dose increments until a 
≥ Grade 2 AE related to BDTX-189 is observed, or until the 200 mg QD dose cohort is complete 
(see Section 4.3).  The projected dose range expected to be associated with antitumor activity in 
humans is 6.7-13 mg/kg/day which compares favorably with the HNSTD of 20 and 
30 mg/kg/day observed in dog and rat, respectively. 
Given that the mechanism of action of BDTX-189 is covalent/irreversible, the totality of 
emerging PK/PDx data will need to be considered in a scenario where the half-life is too short to 
achieve sufficient target engagement/pathway modulation, or where target coverage is under 
predicted in preclinical models (Figure 9).  Therefore, a parallel Dose Escalation of one 
alternative dose schedule (BID) of BDTX-189 may be evaluated. 
Figure 9 
Predicted BDTX-189 Unbound Plasma Concentrations over Time for QD 
and BID Dosing Schedules 
 
1.2. 
Potential Risks and Benefits of the Treatment Regimen 
This is the first in-human study with BDTX-189.  The risks for human patients have been 
estimated based on the results of the preclinical toxicology studies with BDTX-189. 


 
 
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The target organs of toxicology with BDTX-189 based on preclinical data include: 
• Gastrointestinal Effects: Inflammation/hyperplasia/atrophy of the gastrointestinal mucosa 
(esophagus, stomach, duodenum, jejunum, ileum, cecum) consistent with a primary 
irritant effect in the proximal gastrointestinal tract in dogs with associated secondary 
changes within the mesenteric lymph nodes and pancreas, increases in total WBC in both 
species and increases in platelet counts in dogs at the higher dose levels.  This was 
associated with clinical signs of inappetence, vomitus, and liquid/loose feces in rat and/or 
dog.  All of these BDTX-189-related findings completely or partially resolved following 
a 14-day recovery period. 
Toxicology findings of uncertain relationship to BDTX-189 include: 
• Kidney: Slight papillary inflammation of unknown pathogenesis in 1 dog at 
40 mg/kg/day. 
• Pancreas: Minimal-to-slight interstitial edema in dogs at 20 and 40 mg/kg/day considered 
secondary to gastrointestinal inflammation. 
Adverse events observed in the dose-escalation portion of the ongoing Phase 1 study:  
• Gastrointestinal disorders including nausea, vomiting and diarrhea, some at Grade 3 
severity 
• Hepatic test abnormality, including Grade 3 ALT and/or AST elevations and Grade 2 
blood bilirubin elevation 
Despite the 6-fold in vitro selectivity of BDTX-189 for ErbB mutations versus WT 
, the 
potential for typical 
-related class AEs such as cutaneous toxicities and diarrhea cannot be 
excluded.  Moreover, due to the potent anti-
 effects the potential for cardiac dysfunction is 
a theoretical possibility.  The potential risks associated with BDTX-189 treatment based on 
observed toxicology findings and potential class-effects are considered monitorable and 
reversible in patients.  Please refer to the BDTX-189 IB for further details regarding the potential 
risk associated with the use of BDTX-189. 
Patients will be monitored periodically as per the Schedule of Assessments (Table 1, Table 2, 
and Table 3) with physical examinations, hematology, chemistry, coagulation, urinalysis, 
electrocardiograms (ECGs), and cardiac function.  Women of child-bearing potential (WOCBP) 
and  male patients must agree to use a highly-effective method of contraception during the study 
and for at least 90 days after the last dose of study treatment. 
Currently, 
-directed therapies are only approved for patients with tumors harboring 
 
amplifications and not for 
 mutations.  Allosteric ErbB mutations are mostly resistant to 
approved 
-directed therapies at achievable systemic exposures in humans.  There remains a 
significant unmet medical need for drugs that target allosteric ErbB mutations including 
 
.  The preclinical data for BDTX-189 demonstrate antitumor activity across a range of 
allosteric ErbB mutants both in vitro and in vivo evidenced by both TGI and regression.  The 
data obtained to date for BDTX-189 are regarded as sufficient to justify evaluation of the 
objectives for the planned study in patients with advanced solid malignancies.  BDTX-189 is an 
investigational drug and currently there are no proven benefits. 


 
 
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1.2.1. 
Precautions and Risks Associated with BDTX-189 
Dose-limiting toxicities have included reversible Grade 3 ALT/AST increases, Grade 3 diarrhea 
(lasting >24 hours), Grade 3 dehydration, and intolerable Grade 2 and Grade 3 nausea and 
vomiting.  Gastrointestinal disorders increased in frequency and severity with increasing doses.  
A total of 72% of the patients across all dose levels experienced treatment-related 
gastrointestinal TEAEs, of which 19% were Grade 3 severity. A total of 14% experienced a 
drug-related skin disorder TEAE. No patients have experienced a treatment-related TEAE of 
Grade 4 or 5 severity. Further details are described in the IB. 


 
 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Objective 
The primary objectives of this study are to: 
Part A 
• Determine the recommended Phase 2 dose (RP2D) and schedule of BDTX-189 as a 
single agent administered orally (PO) in patients with advanced solid malignancies.   
Part B 
• Assess the antitumor activity of BDTX-189 as a single agent in patients with allosteric 
 mutations, including 
 mutations.   
2.2. 
Secondary Objectives 
The secondary objectives of this study are to: 
Part A and B 
• Assess the safety and tolerability of BDTX-189 as a single oral agent.   
• Investigate the PK of BDTX-189 using population PK (PopPK) methods and explore 
correlations between PK, response, and/or safety findings.   
Part A 
• Establish the PK of BDTX-189 and circulating metabolite profile after a single dose and 
at steady state.   
• Assess the preliminary efficacy and antitumor activity of BDTX-189 as a single oral 
agent.   
• Assess the effect of food on the PK of BDTX-189.   
Part B 
• Assess additional measures of efficacy and antitumor activity of BDTX-189 as a single 
agent.   
• Assess patient outcome by evaluation of electronic patient reported outcomes (ePRO).   
2.3. 
Exploratory Objectives 
The exploratory objectives of this study are to: 
Part A and B 
• Evaluate allosteric ErbB mutations, gene amplifications, and possible markers of drug 
sensitivity and resistance in plasma using ctDNA.   




 
 
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Primary Objective: 
Endpoint/Variable: 
Part A: Evaluate the PDx effects of BDTX-189 
in tumor tissue as determined by ErbB signaling 
pathway proteins 
ErbB signaling pathway proteins in tumor tissue, such as pERK 
Abbreviations: AUC = area under the concentration time curve; BICR = blinded independent central review; CI = confidence 
interval; Cl/F = oral clearance; Cmax = maximum concentration; CR = complete response; CT = computed tomography; CTCAE = 
Common Terminology Criteria for Adverse Events; ctDNA = circulating tumor DNA; DCR = disease control rate; DLT = dose 
limiting toxicity; DOR = duration of response; ECG = electrocardiogram; 
; ePRO = 
electronic patient reported outcomes; EQ-5D-5L = EuroQol Group’s 5-domain 5-level questionnaire; FACT = Functional 
Assessment of Cancer Therapy; FACT-G = Functional Assessment of Cancer Therapy-General; FBSI = Functional Assessment 
of Cancer Therapy Breast Symptom Index; FLSI = Functional Assessment of Cancer Therapy Lung Cancer Symptom Index; 
 Ka = first-order absorption rate constant; MRI = magnetic resonance 
imaging; NCCN = National Comprehensive Cancer Network; NCI = National Cancer Institute; OS = overall survival; PDx = 
pharmacodynamics; pERK = phosphorylated extracellular regulated kinase; PFS =  progression-free survival; PK = 
pharmacokinetics; PO = by mouth; popPK = population pharmacokinetics; PR = partial response; PROMIS = Patient Reported 
Outcomes Measurement Information System; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended 
Phase 2 dose; t1/2 = elimination half-life; TEAEs = treatment-emergent adverse events; Tmax = time for maximum concentration; 
Vd/F = oral volume of distribution. 


 
 
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3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
3.1. 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the research study: 
1. Signed and dated written informed consent prior to any study-specific procedures.   
2. Female or male patients age ≥18 years at the time of providing voluntary written 
informed consent.   
3. Histologically- or cytologically-confirmed locally advanced or metastatic solid tumor 
with documented recurrence or disease progression from standard anticancer therapy in 
the advanced/metastatic setting.   
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 
(Appendix A).   
5. Minimum life expectancy of ≥3 months.   
6. Ability to swallow BDTX-189 tablets.   
7. All toxicities from prior therapy (except alopecia, Grade 2 neuropathy, or Grade 2 
hypothyroidism) must have resolved to ≤ Grade 1 according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE Version 5.0) 
prior to baseline.  Pneumonitis due to prior therapy or radiation must be totally resolved.  
Patients with Grade 2 neuropathy, Grade 2 hypothyroidism, or other toxicities that are 
asymptomatic or adequately managed with stable medication may be eligible with 
approval by the Sponsor.   
8. For women of child-bearing potential (WOCBP), documentation of negative serum 
pregnancy test (beta-human chorionic gonadotropin [β-hCG]) within 7 days prior to 
baseline (Appendix C).   
• Note: WOCBP is defined as fertile, following menarche and until becoming post-
menopausal (no menses for 12 months without an alternative medical cause) 
unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy).   
9. For WOCBP and male patients whose sexual partners are WOCBP, agreement to use a 
highly effective method of contraception during the study and for at least 90 days after 
the last dose of study treatment.  Male patients must also refrain from donating sperm 
during their participation in the study (Appendix C).   
• Note: Highly effective birth control includes: 1) oral, implantable, or injectable 
combined hormonal (estrogen and progesterone containing) or progesterone only 
contraceptive associated with inhibition of ovulation; 2) intrauterine device; 3) 
intrauterine hormone-releasing system; or 4) bilateral tubal occlusion, 
vasectomized partner or sexual abstinence.   
Part A Only 
10. No standard therapy available according to the Investigator.   


 
 
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11. For the dose-escalation portion, patients with solid tumors with alterations that may be 
associated with antitumor activity based on preclinical data for BDTX-189 such as: 
a. 
 or 
 mutation(s) 
b. 
 or 
 mutation 
c. 
 amplified or overexpressing tumor 
d. 
 mutation  
Mutations must have been determined by a validated NGS test routinely used by each 
institution using tissue and/or plasma and performed in a Clinical Laboratory 
Improvement Amendments (CLIA)-certified or equivalent laboratory.  A list of eligible 
validated oncogenic mutations from 1 of the 7 MTCs is provided in Appendix I. 
Part A Safety Expansion Only 
12. Patients with one of the following mutations and tumor pairs: 
a. 
 mutation in patients with NSCLC, breast cancer, biliary tract 
cancer, or cervical cancer 
b. 
 or 
 mutation in patients with NSCLC  
c. 
amplified or overexpressing tumor from the following cancer types: breast, 
gastric, gastroesophageal, colorectal, endometrial, biliary tract, cancer of 
unknown primary (CUP), and NSCLC   
Mutations must have been determined by a validated NGS test routinely used by each 
institution using tissue and/or plasma and performed in a CLIA-certified or equivalent 
laboratory.  A list of eligible validated oncogenic mutations from 1 of the 7 MTCs are 
provided in Appendix I.   
Note: The Sponsor reserves the right to prioritize tumor/genomic alteration pairs and to 
cap enrollment for any of these based on the Sponsor’s portfolio decision-making 
process. 
13. Mandatory archival tumor tissue or willing to undergo pretreatment biopsy if no archival 
tissue available (Section 5.7.1).   
14. Measurable disease according to RECIST version 1.1 (Appendix B).   
Part B Only 
15. Patients with locally advanced or metastatic:  
a. NSCLC who have received at least one prior platinum-containing regimen (with or 
without an anti-PD-[L]1 antibody) and no more than 2 prior regimens for advanced 
NSCLC.  Patients with no prior therapy who refuse standard therapy may also be 
eligible following discussion and approval by the Sponsor’s Medical Monitor.   
b. Solid tumor other than NSCLC who have received at least one and no more than 3 
prior regimens for advanced cancer.   




 
 
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ii. Hemoglobin ≤8.5 g/dL or 5.28 mmol/L.   
iii. Platelet count ≤75,000/μL.   
2. Significant cardiovascular disease, including: 
a. Cardiac failure New York Heart Association Class III or IV (Appendix D), or left 
ventricular ejection fraction (LVEF) <50% or below the lower limit of the 
Institution’s normal range.   
b. Myocardial infarction, severe or unstable angina within 6 months prior to 
baseline.   
c. Significant thrombotic or embolic events within 3 months prior to baseline 
including, but not limited to, stroke or transient ischemic attack.  Catheter-related 
thrombosis and deep vein thrombosis are not a cause for exclusion.   
d. History or presence of any uncontrolled cardiovascular disease.   
e. Personal or family history of long QT syndrome.   
3. ECG findings obtained using the study site’s ECG machine-derived measurements, 
meeting any of the following criteria: 
a. Evidence of second- or third-degree atrioventricular block.   
b. Clinically significant arrhythmia (as determined by the Investigator).   
c. QTc interval of >470 msec as calculated according to Fridericia’s formula 
(QTcF = QT/R to R interval0.33).   
4. Leptomeningeal or untreated central nervous system (CNS) malignancies (primary or 
metastatic); patients with asymptomatic CNS metastases who have undergone surgery or 
radiotherapy 4 weeks prior to C1D1 and who are on a dose of prednisone of no more than 
10 mg or equivalent will be eligible for Part A of the trial.   
5. Received other recent antitumor therapy, including:  
a. Investigational therapy administered within the 28 days prior to baseline or 
5 half-lives, whichever is shorter.   
b. Any standard chemotherapy, targeted therapy (TKI or mAB), or radiation within 
14 days prior to baseline.   
c. Any antineoplastic mAbs within 21 days or checkpoint immunotherapy 
(including, but not limited to, pembrolizumab, nivolumab, atezolizumab, or 
durvalumab) within 3 months prior to baseline.   
6. Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline.   
7. Known concurrent 
 mutation.   
8. Known tumor-harboring resistance mutations including 
 or 
 
mutations or 
 mutations.   
9. Prior documented treatment response (i.e., complete response [CR], partial response 
[PR], or stable disease [SD] lasting ≥24 weeks by Response Evaluation Criteria in Solid 


 
 
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Tumors [RECIST] v1.1) to approved or investigational 
 or 
 therapies (e.g., 
afatinib, lapatinib, dacomitinib, neratinib, trastuzumab deruxtecan, poziotinib, 
mobocertinib, amivantamab).   
• Patients with or without tumor response discontinuing after 8 weeks or less of 
therapy due to toxicity may be considered after discussion with the Sponsor 
Medical Monitor.   
• Patients with an NGS test (tissue or plasma) obtained within 8 weeks of Baseline 
which does not include any mutations listed in Exclusion Criteria 7 or 8 may be 
considered after discussion with the Sponsor Medical Monitor. 
10. Major surgery within 4 weeks before baseline or scheduled for surgery during projected 
course of the study.   
11. Received a transfusion of whole blood or red blood cells within 1 week, or platelet 
transfusion within 2 weeks before baseline.   
12. Any history of concomitant condition (e.g., alcohol abuse or psychiatric condition) that, 
in the opinion of the Investigator, would compromise the patient’s ability to comply with 
the study or interfere with the evaluation of the safety and efficacy of the study drug.   
13. Known concurrent malignancy that is expected to require active treatment within 2 years 
and that may interfere with the interpretation of the efficacy and safety outcomes of the 
study in the opinion of the treating Investigator confirmed by the Medical Monitor.  Prior 
malignancy that is at a low risk of progression or recurrence (e.g., superficial bladder 
cancer, non-melanoma skin cancers, or low-grade prostate cancer not requiring therapy) 
is allowed.   
14. Known active hepatitis B or C infection and/or known human immunodeficiency virus 
(HIV) carrier.   
15. Any history (within 6 months) or presence of poorly controlled gastrointestinal disorders 
that may interfere with absorption of the study drug including delayed gastric emptying, 
chronic diarrhea associated with intestinal malabsorption, ulcerative colitis or Crohn's 
disease that requires steroid therapy at any dose, refractory nausea and vomiting, and/or 
prior surgical procedures affecting absorption or requirement of intravenous alimentation.   
16. Taking medications or herbal supplements that are known potent CYP3A4 
inhibitors/inducers (including St. John’s wort, kava, ephedra [ma huang], ginkgo biloba, 
dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, ginseng, and double-strength 
grapefruit juice) within 14 days before the start of treatment through permanent 
discontinuation of study treatment (See Appendix E).   
17. Taking medications that are known to have a risk to cause QT interval and/or Torsades de 
pointes within 14 days before the start of treatment through permanent discontinuation of 
study treatment (Appendix F).   
18. Women who are pregnant or breast-feeding.   
3.3. 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 


 
 
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• 
Disease progression (patients who are receiving clinical benefit in the opinion of the 
treating Investigator may be allowed to stay on study after consultation with the Medical 
Monitor).   
• 
Intolerable toxicity or abnormal laboratory values thought to be related to drug toxicity.   
• 
Conditions requiring therapeutic intervention not permitted by the protocol.   
• 
Intercurrent illness that may interfere with the patient’s ongoing participation in the study 
(this will be at the Investigator’s discretion).   
• 
Inability of the patient to comply with study requirements.   
• 
Patient lost to follow-up.   
• 
Patient requests to discontinue treatment.   
• 
Patient withdraws consent from study participation altogether.   
• 
Pregnancy.   
• 
Study termination.   
After discontinuation from protocol treatment, patients must be followed for AEs for 30 days 
after their last dose of study drug.  All new AEs occurring during this period must be reported 
and followed until resolution unless, in the opinion of the Investigator, these values are not likely 
to improve because of the underlying disease.  In this case, the Investigator must record his or 
her reasoning for this decision in the patient’s medical records and indicate on the AE pages of 
the electronic case report form (eCRF) that the outcome is not resolved. 
All patients who have Grade 3 or 4 laboratory abnormalities (per NCI CTCAE Version 5.0) at 
the time of discontinuation must be followed until the laboratory values have returned to Grade 1 
or 2 unless it is, in the opinion of the Investigator, not likely that these values are to improve.  In 
this case, the Investigator must record his or her reasoning for making this decision in the 
patient’s medical records and indicate on the AE pages on the eCRF that the outcome is not 
resolved. 


 
 
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4. 
STUDY DESIGN 
This is a Phase 1/2, open-label, 2-part study of an inhibitor of allosteric ErbB mutations, 
BDTX-189, given as a single oral agent.  The study schema is shown in Figure 10. 
4.1. 
Part A (Phase 1 - Dose Escalation and Safety Expansion) 
Part A (Phase 1) is designed to determine the RP2D and schedule of BDTX-189 as a single 
agent.  The RP2D will be based on the safety, tolerability, PK, food effect, and preliminary 
antitumor activity of BDTX-189 and will not exceed the MTD (see Section 4.3.3). 
BDTX-189 will be given PO QD on a 21-day schedule in escalating doses.  Accelerated titration 
has been performed with single-patient cohorts at 25, 50, 100, and 200 mg QD followed by 
multiple-patient cohorts of 400, 800, and 1200 mg QD in fasting state. After the SRC determined 
1200 mg QD fasting exceeded the MTD, 800 mg, and 1000 mg QD administered with a meal 
(i.e., NF) were evaluated.   
In addition, a parallel, dose-escalation of BDTX-189 being administered BID is being evaluated.  
The SRC determined to initiate the BID evaluation at 800 mg BID, which was subsequently de-
escalated to 600 mg BID.  A dose of 400 mg BID will also be evaluated.   
The Safety Expansion cohort(s) at the MTD or lower dose for the QD and/or BID schedule of up 
to approximately 48 additional patients (including a minimum of 12 patients who may receive 
the smaller and reformulated 200 mg tablet strength [see Section 6.1.1]) will be enrolled to 
further evaluate the safety, PK, and preliminary efficacy of BDTX-189 while administrative 
steps are taken to open enrollment in Part B of the study. Patients in Part A who initiated 
treatment with the larger 200 mg tablet may be switched to the smaller and reformulated 200 mg 
tablet at the beginning of their subsequent cycles as instructed by the Sponsor. 
After the SRC deemed the 400 mg QD dose regimen was tolerable, a fed (high- or low-fat 
meal)/fasted randomized crossover, single-dose, lead-in phase was initiated (in up to 16 PK-
evaluable patients) to assess the effect of food on the PK of 400 mg BDTX-189 (see Table 1 and 
Section 5.3.1).  Enrollment of the Food-Effect cohort and next dose cohort (800 mg QD Dose 
Expansion cohort) was done in parallel with priority for enrollment given to the 800 mg QD 
cohort.   
Patients in Part A who terminate participation in the study for any reason other than DLTs before 
completing Cycle 1 and patients who do not receive at least 75% of the planned doses of BDTX-
189 in Cycle 1 for any reason other than DLT-related interruptions will be considered non-
evaluable (NE) for DLTs, and additional patients may be enrolled to ensure an adequate number 
of DLT-evaluable patients.  Additional patients may also be enrolled if there are patients who are 
deemed NE for food effect PK assessment. 
Patients who experience a DLT but who, in the opinion of the Investigator, are deriving clinical 
benefit will be permitted to continue treatment with BDTX-189 at a lower dose that has been 
demonstrated to be well tolerated upon resolution of the DLT.  In total approximately 
128 patients will be enrolled in Part A. 






 
 
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4.3. 
Treatment Plan 
BDTX-189 
BDTX-189 will be provided as tablets for oral administration in dose strengths of 100 and 200 
mg.  Additionally, a smaller and reformulated 200 mg tablet will be administered to some 
patients at select sites enrolling in the Safety Expansion of Part A and all patients enrolling onto 
Part B.   
Prior to exceeding the MTD for the QD schedule, patients received BDTX-189 in a fasted state.  
As of January 2021, based on the recommendation of the SRC (details provided in 
Section 1.1.7), all patients will receive BDTX-189 with approximately 240 mL water within 
30 minutes of completing a meal (Section 6.1.2).  The time of day for BDTX-189 administration 
should be consistent.  For patients receiving BDTX-189 BID, the 2 doses should be separated by 
at least 10 hours.  
Patients enrolling into the Food Effect cohort will be dosed in the fed/fasted state as per Table 1 
and Section 5.3.  On scheduled PK collection days (Cycle 1 Day 1 and Cycle 1 Day 15 for 
Part A, and Days -4 and -1 for the Food Effect Cohort), patients will be instructed to wait until 
they arrive at the study center to take their study drug when told.   
In Part B, patients will be administered BDTX-189 at the RP2D identified during Part A (800 mg 
QD, non-fasting). 
If the patient misses a dose of study drug, the patient should take the dose as soon as possible but 
not less than 12 hours before the next dose is due for QD dosing.  If the next dose is due in less 
than 12 hours, the patient should skip the missed dose and take the next dose as scheduled.  If the 
patient in a BID cohort misses a dose of study drug, the patient should take the dose as soon as 
possible but not less than 6 hours before the next dose is due for BID dosing.  If the next dose is 
due in less than 6 hours, the patient should skip the missed dose and take the next dose as 
scheduled. 
If vomiting occurs more than 30 minutes after taking the study treatment, the patient should be 
instructed not to retake that dose.  Patients should take the next scheduled dose of BDTX-189.  If 
vomiting persists, the patient should contact the Investigator. 
BDTX-189 dosing compliance will be reviewed with the patient at the beginning of each new 
treatment cycle when the study drug is dispensed.  A cycle will be 21 days.  All patients will be 
required to complete a paper dosing diary, which must be returned to the clinic for review at each 
visit.  The patient should be instructed to record each date and time the dose(s) were taken in the 
dosing diary.  If a dose is missed, the reason must be noted in the diary. 
Patients should be advised to return any unused BDTX-189 in the original bottles, in addition to 
returning any empty bottles.  Any remaining empty study drug bottles and dosing diaries will be 
given to the study staff at the End-of-Treatment (EOT) visit. 
No routine anti-diarrheal agents will be given preemptively.  However anti-diarrheal agents 
should be administered in the event of diarrhea to manage the symptoms (see Table 8).  
Prophylactic anti-emetics are allowed for nausea and/or vomiting.  Oral ondansetron may be 
used after consultation with the Sponsor. 


 
 
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Table 5 
Dose Levels Projected for Evaluation (Part A) 
QD Cohort -  
Dose Level 
Total Daily Dose (QD) 
BID Cohort – Dose 
Level 
Total Daily Dose (BID)a 
1 (starting dose) 
25 mg 
 
2 
50 mg 
3 
100 mg 
4 
200 mg 
5 
400 mg 
1 (earliest starting dose) 
400 mg 
6 
800 mg 
2 
800 mg 
7 
1200 mg 
3 
1600 mg 
8 
1600 mg 
4 
2000 mg 
Abbreviations:  BID = twice daily; QD = once daily 
a Alternative dosing schedule (BID) evaluation may or may not be initiated.  If the BID schedule is evaluated, the first dose level 
may not be initiated until dose level 4 of the QD schedule is declared tolerable by the Safety Review Committee.  The QD and 
BID schedule, if opened, will be assessed and escalated independently. 
4.3.1. 
Dose-Escalation Procedure 
The actual number of dose cohorts to be explored in this study will depend on determination of 
the MTD based on DLTs reported during the DLT evaluation period (Day 1 to Day 21 in Cycle 1 
[Part A]). 
In order that sufficient PK data are collected at doses below the MTD, additional patients may be 
enrolled at lower doses. 
The Bayesian Optimal Interval Design 
A Bayesian optimal interval (BOIN) design (Liu and Yuan 2015; Yuan et al. 2016) will be used 
to find the MTD (Appendix G).  For this study, the target toxicity rate for the MTD will be 
ɸ = 0.3 and the maximum sample size will be 36 evaluable patients for the QD schedule, 
excluding patients in the accelerated titration step.  The BOIN study design is described in the 
following steps: 
1. Accelerated titration will be performed as follows: the first patient will be treated at QD dose 
level 1.  If no ≥Grade 2 AE related to BDTX-189 is observed during Cycle 1, the dose will 
be escalated to the next higher level for the next patient enrolled.  One additional patient may 
be enrolled to ensure at least 1 patient is DLT-evaluable.  This one-patient-per-dose 
escalation process will be continued until any ≥Grade 2 AE related to BDTX-189 is 
observed, and then an additional 2 patients will be treated at the dose at which the AE is 
observed.  If no ≥Grade 2 drug-related AE is observed by dose level 4 (200 mg QD), then 
enrollment into dose level 5 will proceed.  Thereafter, patients will be treated in cohorts as 
described in steps 2 and 3. 
2. To assign a dose to the next cohort of patients, dose escalation/de-escalation will be 
conducted according to the rules in Table 6, which minimize the probability of incorrect dose 
assignment. 




 
 
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the MTD that will be selected.  If there are ties, the higher dose level will be selected when the 
isotonic estimate is lower than the target toxicity rate, and the lower dose level will be selected 
when the isotonic estimate is greater than or equal to the target toxicity rate. 
Once the MTD has been determined (MTD may be QD or BID), up to 48 additional patients 
(including 12-24 patients for PK evaluation of a smaller and reformulated 200 mg tablet) may be 
enrolled at the MTD or a lower dose if deemed relevant, to obtain additional experience with 
safety and efficacy.  The elimination boundaries in Appendix H will be used for toxicity 
monitoring. 
BID Dose Schedule Evaluation 
In the event that PK, tolerability, or PDx analysis suggests that a more frequent daily dosing 
schedule should be explored, a BID dose schedule will be evaluated and a separate BOIN design 
will be used to find the MTD using that dosing schedule.  The design parameters will depend on 
the specific PK/PDx and tolerability results and the cumulative observations from the QD Dose 
Escalation study.  The BID schedule will not be initiated until dose level 4 (200 mg QD) of the 
QD schedule has been deemed tolerated or until the MTD has been determined for the QD 
schedule (see Table 5).  The BID schedule may also be initiated at higher dose levels as 
determined by the SRC based on emerging safety and PK data.  Should a Dose Escalation for the 
QD schedule be eliminated before reaching the highest dose, then BID Dose Escalation may be 
pursued independently. 
The target toxicity rate for the MTD will remain ɸ = 0.3, and patients will be enrolled and treated 
in cohorts with no accelerated titration phase.  The Dose Escalation/de-escalation rules will be 
the same as shown in Table 6 and Appendix H. 
If 4 dose levels are evaluated and the maximum sample size is 24, the study will continue until 
24 patients have been treated or if the number of patients treated at the current dose reaches 15. 
4.3.2. 
Dose-limiting Toxicity 
Toxicity will be assessed using the NCI CTCAE Version 5.0 unless otherwise specified. 
A toxicity will be considered dose-limiting (unless clearly attributable to an extraneous cause, 
such as underlying disease) if it occurs during the first cycle (21 days) of treatment with 
BDTX-189.  Dose-limiting toxicities (DLTs) will be defined as follows: 
• Any death not clearly due to the underlying disease or extraneous causes.   
• Hematologic toxicity 
- 
Grade 4 neutropenia or thrombocytopenia for >7 days or febrile neutropenia.   
- 
Grade 3 thrombocytopenia associated with bleeding or requiring a platelet 
transfusion.   
- 
Grade ≥4 anemia.   
• Non-hematologic toxicity of ≥ Grade 3 (at any time during treatment) that, in the 
judgment of the Investigator, is dose-limiting except for: 
- 
Grade 3 fatigue lasting <1 week.   
- 
Grade 3 nausea, vomiting, or diarrhea lasting <5 days without adequate 
supportive care.   


 
 
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- 
Grade 3 nausea, vomiting, or diarrhea lasting <24 hours with adequate supportive 
care.   
• The following non-hematologic laboratory abnormalities: 
- 
Baseline Grade ≤1 ALT or AST: any drug -related Grade ≥3 abnormality of ALT 
and/or AST or increase in ALT or AST >3 × ULN with a concurrent increase in 
total bilirubin >2 × ULN (per Hy’s Law).   
- 
Baseline Grade ≥2 ALT or AST due to liver metastases: any drug-related ALT 
and/or AST >2 × baseline or ≥10 × ULN.   
• Dose reduction during Cycle 1 due to an AE related to BDTX-189.   
• Delay of starting Cycle 2 for >2 weeks if due to an AE related to BDTX-189.   
• Interruption of BDTX-189 dosing for more than 7 days during Cycle 1, if due to a drug-
related AE.   
4.3.2.1. 
Determination of DLT-evaluable Population 
The patient population used for determination of DLTs will consist of patients who have met the 
minimum safety evaluation requirements of the study or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of treatment, the patient receives at 
least 75% of planned total doses of BDTX-189 (i.e., 16 of 21 QD doses or 32 of 42 BID doses 
unless due to dose hold guidelines provided in Table 8) and is observed for at least 21 days 
following the first dose of BDTX-189.  Patients receiving less than 75% of the planned doses of 
BDTX-189 due to drug-related AEs that are not considered a DLT may still be evaluable for 
determination of DLTs. 
If a patient withdraws from treatment during Cycle 1 due to any reason other than DLT and does 
not meet the minimum requirements for inclusion in the DLT-evaluable population described 
above, an additional patient may be enrolled to ensure an adequate number of evaluable patients.  
Patients being evaluated for Food Effect will not be part of the DLT-evaluable population per the 
BOIN design parameters; however, the safety information from these patients will be considered 
when making decisions about Dose Escalation/de-escalation and determination of the RP2D. 
4.3.3. 
Maximum-tolerated Dose 
The BOIN design will be used to find the MTD in this study.  The target toxicity rate for the 
MTD will be ɸ = 0.3 and the maximum sample size will be 36 evaluable patients for the QD 
schedule and 24 patients for the BID schedule, should that be explored.  Please see Section 4.3.1 
and Table 6 for complete details. 
4.3.4. 
Safety Expansion after Determination of the Maximum-Tolerated Dose 
As described in Section 1.1.7, the MTD and preliminary RP2D is 800 mg for the QD schedule.  
Once the Safety Expansion opens for enrollment, up to 48 additional patients (including patients 
for PK evaluation of a smaller and reformulated tablet [see below]) will be enrolled at the MTD 
or a lower dose for either the QD and/or the BID schedule to further characterize the safety, PK, 
and efficacy profile.  The MTD will be considered the recommended dose unless there is a lower 
dose that provides adequate exposure and biologic activity with more favorable tolerability. 


 
 
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A smaller and reformulated 200 mg tablet will be introduced and may be supplied to some 
patients during the Safety Expansion of Part A; these tablets will be available to all patients 
enrolling on Part B.  A minimum of 12 patients from selected study sites may undergo PK 
evaluation on C1D1 and C1D15 (see Section 5.6) during the Safety Expansion period and/or 
Part B.   
Should the PK parameters from these smaller and reformulated tablets be consistent with data 
from the larger tablets, additional PK evaluation can be performed in newly enrolled patients on 
C1D1 and C1D15 and/or by switching patients from the larger tablets to the smaller and 
reformulated 200 mg tablets to further characterize the PK.  The latter subset of patients in 
Part A who initiated treatment with the larger 200 mg tablet may be switched to the smaller and 
reformulated 200 mg tablet at the beginning of the subsequent cycle.  Detailed PK sampling will 
be collected on Day 15 of that subsequent cycle according to Table 10, to provide additional 
exposure data.   
4.3.5. 
Dose Modifications 
If toxicity occurs, the toxicity will be graded using the NCI CTCAE Version 5.0, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof.  
Dose adjustments will be based on the organ system exhibiting the greatest degree of toxicity. 
Specific criteria for interruption, re-initiation, dose reduction, and/or discontinuation of 
BDTX-189 are listed in Table 8.  All interruptions or modifications must be recorded on the AE 
and drug administration eCRFs.  Appropriate clinical experts must be consulted as deemed 
necessary. 
The Investigator will evaluate which AEs are attributed to the study drug and adjust the dose of 
the drug as recommended below.  All dose modifications must be based on the worst preceding 
toxicity (CTCAE Version 5.0). 
Patients whose treatment is delayed due to AEs may continue treatment if the AE resolves within 
21 days of onset.  Any patient who requires a treatment interruption of more than 21 days due to 
AEs will be discontinued from study treatment unless the Investigator and the Medical Monitor 
agree that continued treatment at the appropriate dose is in the best interest of the patient. 
A maximum of 2 dose reductions are allowed in this study.  Table 7 outlines acceptable dose 
reductions for patients in the Safety Expansion of Part A or Part B, who are enrolling after the 
implementation of Amendment 3.  Once the dose of BDTX-189 has been reduced because of 
toxicity, all subsequent cycles must be administered at that lower dose level unless further dose 
reduction is required.  The patient will be withdrawn from study treatment if further toxicity 
meeting the requirement for dose reduction occurs.  Dose reduction below the initial starting 
dose levels for QD and BID in Part A, respectively, is not allowed.  Otherwise, the patient must 
be removed from treatment. 
Recommended BDTX-189 dose modifications are presented in Table 8. 
Table 7 
Dose Reduction Levels for BDTX-189 Administered Once or Twice Daily 
Original dose 
800 mg QD 
400 mg BID 
Dose level –1 
600 mg QD 
300 mg BID 


 
 
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Dose level –2 
400 mg QD 
200 mg BID 
Table 8 
Dose Modification Guidelines for BDTX-189-related Adverse Events 
Recommended Dose Modifications  
Worst toxicity 
NCI CTCAE v5.0 Grade (value) 
Recommended dose modification 
any time during a cycle of therapy 
Renal 
Serum creatinine 
≤1.5 × ULN 
Maintain dose level 
  
 
Grade 2 (>1.5 to 3 × ULN) 
Omit dose until resolved to baseline, then  
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 
Grade 3 (>3.0 to 6.0 × ULN)  
Discontinue patient from study treatment 
Grade 4 (>6.0 × ULN) 
Discontinue patient from study treatment 
Hepatic 
Total bilirubin 
<1.5 × ULN 
Maintain dose level 
 
 
Grade 2 (>1.5 to 3 × ULN if 
baseline was normal; >1.5 to 3.0 × 
baseline if baseline was abnormal) 
Omit dose until resolved to baseline, then  
• 
If resolved ≤7 days, then maintain dose level 
• 
If resolved >7 days, then  1 dose level 
Grade 3 (>3.0 to 10.0 × ULN if 
baseline was normal; >3.0 to 10.0 × 
baseline if baseline was abnormal) 
Omit dose until resolved to baseline, then  
• 
If resolved ≤7 days, then  1 dose level   
• 
If resolved >7 days and discontinue patient from study treatment  
Grade 4 (>10.0 × ULN if baseline 
was normal; >10.0 × baseline if 
baseline was abnormal) 
Discontinue patient from study treatment 
Note: If Grade 3 or 4 hyperbilirubinemia is due to the indirect 
(unconjugated) component only and hemolysis has been ruled out as the 
etiology as per institutional guidelines (e.g., review of peripheral blood 
smear and haptoglobin determination), then  1 dose level and continue 
treatment at the discretion of the Investigator 
AST or ALT 
Grade 1 (>ULN to 3.0 × ULN if 
baseline was normal; >1.5 to 3.0 × 
baseline if baseline was abnormal) 
Maintain dose level 
Grade 2 (>3.0 to 5.0 × ULN if 
baseline was normal; >3.0 to 5.0 × 
baseline if baseline was abnormal) 
Maintain dose level 
Grade 3 (>5.0 to 20.0 × ULN if 
baseline was normal; >5.0 to 20.0 
× baseline if baseline was 
abnormal) 
Omit dose until resolved to ≤ Grade 1 (or ≤ Grade 2 if liver metastases 
present), then either maintain dose level (if Grade 3 lasted ≤7 days) or  1 
dose level (if Grade 3 lasted >7 days) 
Grade 4 (>20.0 × ULN if baseline 
was normal; >20.0 × baseline if 
baseline was abnormal) 
Discontinue patient from study treatment 


 
 
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Recommended Dose Modifications  
Worst toxicity 
NCI CTCAE v5.0 Grade (value) 
Recommended dose modification 
any time during a cycle of therapy 
Combination of bilirubin and AST/ALT 
Total bilirubin ≥2.0 × ULN and 
ALT or AST ≥3.0 × ULN 
(Potential Hy’s Law) See Section 
8.2.4 for further details 
1st occurrence: Omit dose and repeat tests 2-3 times a week until all 
abnormal lab results resolved to ≤ Grade 1 (or baseline), then  1 dose 
level 
2nd occurrence: Omit dose and discontinue patient from study treatment 
Diarrhea 
 
Grade 1 
Maintain dose level. Stop treatment with concomitant medications that 
may cause diarrhea (e.g., laxatives).  Administration of standard doses of 
loperamide should be initiated. 
Grade 2 
Optimize anti-diarrheal medication.  Temporarily interrupt BDTX-189 
until resolved to Grade ≤1.  Resume same dose level unless associated 
with complicating signs/symptoms, in which case consider  1 dose level. 
Grade 3 
Optimize anti-diarrheal medication.  Temporarily interrupt BDTX-189 
until resolved to Grade ≤1.  If the severity lasts <24 hours during Cycle 1, 
resume at the same dose level.  If the severity persists for >24 hours or 
resumes, then  1 dose level. 
Grade 4 
Discontinue patient from study treatment 
Skin rash 
Grade 1 
Maintain dose level.  Consider initiation of topical emollients, 
antihistamines in the case of pruritus, and/or topical (mild strength) 
corticosteroid creams 
Grade 2 
Maintain dose level at first occurrence and monitor rash closely.  Initiate 
rash treatment if not already done.  If rash worsen or reoccurs within 14 
days, interrupt BDTX-189 until resolved to Grade ≤1, then  1 dose level. 
Grade 3 
At first occurrence, interrupt BDTX-189 administration and apply topical 
emollients, antihistamines, and/or high strength corticosteroid creams until 
it resolves to ≤ Grade 1, then the study drug can be reinstated at current 
dose level.  At second occurrence, interrupt BDTX-189 administration 
until resolved to Grade ≤1, then  1 dose level. 
Grade 4 
Study drug administration will be discontinued.  Schedule dermatologist 
evaluation 
Prolonged QTc interval 
Grade 2 QTcF >480 msec and 
≤500 msec 
1. Repeat ECG in triplicate as soon as practical, no later than 7 days 
after the initial ECG.  If the mean QTcF on repeat ECG triplicate is 
≤500 msec and the patient is asymptomatic, then continue study drug 
at the same dose.  Post-dose ECG must be monitored weekly in 
triplicate. 
2. If the mean QTcF on repeat ECG triplicate is >480 and ≤500 msec, 
then consultation with cardiologist (must occur as soon as practical, 
no later than 7 days after the initial ECG). 
3. If the cardiologist confirms a mean QTcF >480 and ≤500 msec is 
drug-related, then  1 dose level.  
Grade 3 QTcF >500 msec or 
QTcF increased by ≥60 msec 
from baseline 
1. Repeat ECG in triplicate approximately 1 hour after the initial ECG 
2. If the mean QTcF on repeat ECG triplicate is >500 msec or increased 
by ≥60 msec from baseline, then omit dose until consultation with 
cardiologist (must occur as soon as practical, no later than 7 days after 


 
 
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Recommended Dose Modifications  
Worst toxicity 
NCI CTCAE v5.0 Grade (value) 
Recommended dose modification 
any time during a cycle of therapy 
the initial ECG).  ECG must be monitored in triplicate at the 
frequency selected at Investigator’s discretion.  
3. If the cardiologist confirms a mean QTcF >500 msec or increase by 
≥60 msec from baseline is drug-related, then  1 dose level.  If 
second occurrence is attributed to BDTX-189, then discontinue 
patient from study treatment. 
Left ventricular systolic dysfunction 
Asymptomatic absolute decrease 
of 10% – 19% in LVEF compared 
to baseline and the LVEF is below 
the Institution’s LLN (e.g., a 
decrease from 60% to 48% is an 
absolute decrease of 12%) 
Interrupt BDTX-189 and repeat evaluation of LVEF within 2 weeks: 
• 
If LVEF recovers to ≥50% or ≥ LLN and 
o 
absolute decrease ≤10% compared to baseline in 21 days, then 
maintain dose level 
o 
absolute decrease >10% compared to baseline in 21 days, then 
 1 dose level after approval of Medical Monitor.  Monitor 
LVEF 2 weeks after resuming, every 4 weeks for 12 weeks and 
subsequently per protocol 
• 
If the LVEF does not recover in ≤21 days, permanently discontinue 
BDTX-189.  Closely monitor LVEF until resolution or for up to 16 
weeks. 
Grade 3-4 
Permanently discontinue BDTX-189.  Closely monitor LVEF until 
resolution or for up to 16 weeks. 
All other BDTX-189 treatment-related adverse events 
Grade 1 or 2 (except fatigue, alopecia, 
and laboratory abnormalities not 
requiring medical intervention 
Maintain dose level if the event is Grade 1 or non-persistent Grade 2.  If 
the event is persistent Grade 2 not responding to a specific therapy, 
consider  1 dose level. 
Grade 3 
Omit dose until resolved to ≤ Grade 1 or baseline level, then  1 dose 
level 
Grade 4 
Discontinue patient from study treatment 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; LLN = lower 
limit of normal; LVEF = left ventricular ejection fraction; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; QTcF = QT interval corrected according to Fridericia’s formula; ULN = upper limit of normal.   
Note: After the MTD was exceeded for the QD and BID schedules in fasted state, subsequent cohorts were evaluated non-fasted 
(fed).  For Dose reduction levels refer to Table 7.  
Intrapatient dose-escalation during Part A may be considered in the absence of ≥ Grade 2 
toxicities related to BDTX-189 in the following circumstance: After a new higher dose level has 
been determined to be tolerated (≤30% DLTs), any patients remaining on study and being treated 
with a lower dose of BDTX-189 may, at the discretion of the Investigator and with agreement of 
the Sponsor, be offered treatment at the new higher tolerated dose once that dose level evaluation 
has been cleared.  During the Safety Expansion and Part B, re-escalation of BDTX-189 
following dose reduction due to toxicities may be considered following discussion and approval 
of Sponsor’s Medical Monitor. 
4.4. 
Treatment Duration 
The start of the study is defined as the date when the first patient in the whole study signs 
informed consent. 
The end of the study is defined as the date of the last visit (including all follow-up visits) of the 
last patient in the whole study. 


 
 
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Patients will be evaluated for toxicities through AE reporting (continuously) and other safety 
assessments, weekly for the first 2 cycles during Part A and at the start of each 2 subsequent 
cycles thereafter.  During Part B, patient’s toxicities will be evaluated through AE reporting 
(continuous) and other safety assessments, weekly for the first 2 cycles and then at the start of 
each cycle for the first 4 cycles and every other cycle thereafter.  Restaging will occur with 
imaging, laboratory chemistries, and tumor markers as defined in the Schedule of Assessments 
(Table 1 and Table 3).  Patients will continue on treatment until progressive disease (PD) as 
defined in Section 7 or intolerance of side effects.  Patients who are receiving clinical benefit in 
the opinion of the treating Investigator may be allowed to stay on study after consultation with 
the Medical Monitor (Section 3.3). 
4.5. 
Concomitant Medications 
Patients will be asked about prior medications during screening and instructed not to take any 
additional medications during the course of the study without prior consultation with the study 
team.  At each visit, the patient will be asked about any new medications he or she is taking or 
has taken from 14 days prior to receiving their first dose of study drug until the 30-Day Safety 
Follow-up visit.  Additionally, for the Safety Expansion portion of Part A and Part B, first 
subsequent anticancer therapy, will be collected as part of PFS/overall survival (OS), from the 
30-day Safety Follow-up visit, and will be obtained every 3 months (±14 days) until 2 years after 
the first study drug dose, death, loss to follow-up, withdrawal of consent, or end of the whole 
trial.    
4.5.1. 
Permitted Concomitant Medications 
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following: 
• Bisphosphonate use or receptor activator of nuclear factor kappa-B (RANK) ligand 
inhibitors, as recommended according to practice guidelines.   
• Oral contraceptives.   
• Hormone-replacement therapy.   
• Megestrol acetate administered as an appetite stimulant.   
• Transfusion of blood or red blood cells and/or prophylactic erythropoietin is permitted for 
the treatment of anemia (transfusion of blood or red blood cells is permitted from C1D1 
until the EOT visit [see Section 3.2 Exclusion Criteria #11]).   
• Transfusion of platelets is permitted from C2D1 until the EOT visit for the treatment of 
thrombocytopenia.   
• Patients may take low-dose warfarin or a Coumadin preparation for maintenance of an 
open port.   
• Concomitant use of corticosteroids at doses up to 10 mg prednisone or equivalent for the 
treatment of inflammatory conditions that are not prohibited by the applicable exclusion 
criteria is permitted.   


 
 
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• Prophylactic anti-emetics and anti-diarrheals are allowed for nausea and/or vomiting and 
diarrhea, per Institutional standards.   
Supportive care and other medications considered necessary for the patient’s safety and 
wellbeing may be given at the discretion of the Investigator, with the exception of those listed in 
Section 4.5.2.   
4.5.2. 
Prohibited Concomitant Medications 
The following treatments are prohibited while in this study: 
• No other investigational therapy should be given to patients.  No anticancer agents other 
than the study treatment should be given to patients from ≤14 days prior to the first dose of 
BDTX-189 for standard chemotherapy and from ≤28 days or 5 half-lives, whichever is 
shorter, for investigational drugs until 30 days after the last dose of BDTX-189.  If such 
agents are required for a patient, then the patient must first be withdrawn from the study.   
• No routine pre-medications will be given during the DLT evaluation period (Day 1 to 
Day 21 in Cycle 1 [Part A]), however, based on emerging clinical experience in earlier 
cohorts/patients, prophylactic administration of medications may be permitted at the 
discretion of the Investigator.   
• Concomitant treatment with any medication that is known to prolong the QT interval 
and/or cause Torsades de pointes is prohibited from 14 days before the start of treatment 
until the EOT visit (see Appendix F).  After study enrollment, if a patient requires use of 
any of these medications, the patient must be removed from study.   
• Drugs known to be strong CYP3A4 inhibitors or inducers are prohibited from ≤14 days 
before the start of treatment until the permanent discontinuation of treatment.  Refer to 
Appendix E for a comprehensive list of agents in these categories.  These agents include, 
but are not limited to: 
o CYP3A4 inhibitors: azole antifungals (ketoconazole, voriconazole and 
itraconazole), macrolide antibiotics (clarithromycin, erythromycin), HIV protease 
inhibitors (indinavir and ritonavir), cimetidine, aprepitant, nelfinavir, nefazodone, 
and double-strength grapefruit juice.   
o CYP3A4 inducers: phenytoin, barbiturates, and rifampicin.   
• Herbal preparations/medications known to be potent inducers of CYP3A4 are not allowed 
from ≤14 days before the start of treatment until permanent discontinuation of treatment.  
These herbal medications include, but are not limited to, St. John’s wort, kava, ephedra (ma 
huang), ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng.   
• Proton pump inhibitors are prohibited from 1 week prior to the start of treatment until the 
discontinuation of treatment.  If the reduction of gastric acidity is essential before or during 
the study at the Investigator’s discretion, the patients may use H2-receptor antagonists or 
antacids (this will not be allowed for patients participating in the Food-Effect Cohort from 
1 week prior to the Day -4 dose until C1D1 [Section 5.3.1]).  If applicable, these agents 
should be taken at least 8 hours before or 2 hours after the daily dose of BDTX-189.   


 
 
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Some prohibited medications may be allowed at the Investigator’s discretion after approval by 
the Medical Monitor when the patient has unmet medical need to continue receiving such 
prohibited medication(s), no suitable alternative treatments are available, and the benefit-risk 
ratio is acceptable in the Investigator’s opinion.  This exemption may not be applied to other 
anti-cancer therapies or other investigational therapies. 
4.5.3. 
Concomitant Medications to be Used with Caution 
The following treatments should be used with caution while in this study: 
• Sensitive substrates of BCRP (e.g., rosuvastatin, sulfasalazine).   
• Strong inhibitors of P-gp (e.g., itraconazole, ritonavir) and BCRP (e.g., curcumin, 
cyclosporine A, eltrombopag).   
A detailed list can be found at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table5-1. 


 
 
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5. 
STUDY ASSESSMENTS AND EVALUATIONS 
5.1. 
Overview 
All patients should visit the study center on the days specified within this protocol.  The C1D1 
visit will determine the visit calendar for the study, and all projected visits will be based on 
the C1D1 visit date.  Study visits must occur according to the study visit schedule and within 
the allowed protocol windows.  Missed doses or dose interruptions should not alter the patient’s 
study visit schedule.  The complete Schedule of Assessments for this study is presented at the 
beginning of this protocol (see Table 1, Table 2, and Table 3).  The key procedures required in 
this study include: 
• Reporting of all AEs occurring after the ICF has been signed.   
• Safety hematology, chemistry, coagulation, and PK samples throughout the study.   
• Baseline and on-treatment blood biomarker assessments.   
• Archived tumor samples or new pretreatment tumor biopsy.   
• Baseline and on-treatment tumor biopsy, if tumor amenable by biopsy (Part A).   
• Tumor assessments (based on computed tomography [CT], positron emission 
tomography [PET], and/or magnetic resonance imaging [MRI] scan) according to 
RECIST Version 1.1 (see Appendix B).   
• ECG measurements (including ECGs time-matched to coincide with detailed PK 
assessments beginning with dose level 4 [200 mg QD]) at baseline and onwards.   
• Cardiac function echocardiography (ECHO) or multigated acquisition scan (MUGA).   
A cycle of treatment is scheduled to last 3 weeks (21 calendar days).  Multiple procedures may 
be scheduled at the same time point relative to BDTX-189 dosing.  Priority should be given to 
PK collection at the time specified.  Vital signs and ECG assessments should be performed prior 
to specimen collections (except where ECG assessments are to coincide with PK sample 
collection). 
5.2. 
Screening 
At enrollment, each potential patient will provide written informed consent ≤28 days prior to 
initiation of treatment and prior to starting any study-specific procedures.  Upon signature of the 
ICF, patients will be assigned a unique patient number as enrollment (screening) occurs. 
The screening assessments described in the Schedule of Assessments (Table 1, Table 2, and 
Table 3) will be collected, reviewed, and determined to be acceptable by the site Principal 
Investigator or designee after obtaining informed consent prior to the initiation of treatment. 
The following screening parameters should be recorded prior to initiation of treatment: 
• Medical history and demographics.   
• Physical examination (including height and weight).   
• ECOG performance status (Appendix A).   


 
 
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• Vital signs (heart rate, systolic and diastolic blood pressure [BP], pulse oximetry, and oral 
or axillary temperature) and weight.   
• ECG.   
• Cardiac MUGA/ECHO (within 28 days; however, no need to repeat during the screening 
if a comparable assessment has been performed ≤6 weeks from the date of consent).   
• Hematology assessments (complete blood count [CBC] with hemoglobin, red blood cell 
count, total WBC count with ANC, absolute lymphocyte count, 5-part differential [% 
neutrophils, % lymphocytes, % or absolute value of: monocytes, basophils, eosinophils] 
and platelet count).   
• Biochemistry assessments (sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN) or blood urea, creatinine, calcium, albumin, total protein, AST, ALT, alkaline 
phosphatase [ALP], total and direct bilirubin, lactate dehydrogenase, amylase, lipase, 
magnesium, phosphorous, and glucose).   
• Coagulation assessments (prothrombin time [PT], activated partial thromboplastin time 
[aPTT], and international normalized ratio [INR]).   
• Urinalysis (protein, glucose, ketones, urobilinogen, occult blood, and microscopic 
sediment evaluation).   
• Screening pregnancy test for WOCBP (serum).   
• Baseline fresh tumor biopsy (or within 28 days prior to C1D1), if tumor is amenable for 
biopsy from dose level 5 (Part A).   
• Archived or new tumor tissue sample (within 28 days if new tumor tissue sample) for 
patients in Part B and only for patients with allosteric ErbB mutations who have archival 
tissue in Part A.   
• CT or MRI for tumor assessment.   
• Genomic results  
o Part A: eligible genomic alteration and allosteric mutation and all co-occurring 
genomic alterations based on NGS testing.   
o Part B: some clinical sites do not routinely perform broad NGS testing of tumor 
tissue.  These sites may need to prescreen some patients for eligible mutations 
which will require separate Sponsor approval and patient consent.   
If the following assessments are performed within the prior 7 days and as part of the screening 
assessments, they do not need to be repeated pre-dose on C1D1: weight, ECOG performance 
status, hematology, clinical chemistry, coagulation, and urinalysis. 
Tumor assessments (scans) should be performed ≤28 days prior to initiation of treatment. 
Relevant concomitant diagnoses and/or therapies present at study entry and/or during screening 
that are relevant to the patient’s safety during the study as judged by the Investigator will be 
recorded in the eCRF (see Section 4.5 for details on concomitant medications). 


 
 
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5.3. 
Assessments During Study Treatment 
Patients will remain on treatment as long as, in the opinion of the Investigator, they are deriving 
benefit and the criteria listed in Section 5.5 are not met.  Please refer to the Schedule of 
Assessments (Table 1, Table 2, and Table 3) for detailed outlines of each visit during the 
treatment period for each part of the study. 
5.3.1. 
Food-effect Assessment (Dose Escalation Part A) 
The effect of food on the PK of BDTX-189 will be assessed in a single dose, fed/fasted 
randomized crossover design.  Based on the projected exposures at the various dose levels, Food 
Effect evaluation is planned at dose level 5 (400 mg QD).  Randomization will be performed by 
Development Innovations at the time of patient registration.  The Food Effect evaluation will be 
executed without disruption of the Dose Escalation and DLT evaluation to the extent feasible.  
Dose level 5 (400 mg QD) will therefore proceed as described in Section 4.3.1 in patients not 
having Food Effect assessed.  Assignment of 3 or more patients to dose level 5 (400 mg QD) for 
DLT assessment will take place according to Section 4.3.2. 
Patients (n = up to 8 per meal type) will be assigned to the Food Effect evaluation as described 
below.  Depending on emerging data, additional patients may be enrolled to meet the 
requirements of a pivotal Food Effect study.  The SRC will decide how to allocate patients but 
should prioritize assignment of patients for DLT evaluation.  Patients evaluated for Food Effect 
will not be counted in the BOIN decision rule.  Should any DLT occur in the Food-effect Cohort, 
this will not be included in the dose escalation/de-escalation rules in Table 6, but the SRC will 
take the information into account for the dose increment/decrement decisions.  Once the Day -1 
assessments are complete, the patients may continue study drug administration on C1D1.  The 
dose will be 400 mg QD unless that dose level has been declared tolerated, and a decision made 
to escalate to dose level 6 (800 mg QD), in which case patients will be assigned to that dose 
level.  Patients included in the Food Effect evaluation will not have additional PK samples 
collected on C1D1. 
Patients will receive BDTX-189 as a single oral dose on Day -4 after fasting for at least 10 hours 
before dosing or immediately after consuming a high-fat breakfast.  Patients will receive BDTX-
189 in the opposite prandial state on Day -1.  BDTX-189 will be administered QD in 21-day 
cycles starting on C1D1.  On the assigned day of PK assessment in the fed state, 30 minutes prior 
to the planned BDTX-189 administration time, patients will be instructed to consume a high-fat 
meal (see below for an example breakfast) and must finish the meal within 30 minutes.  Patients 
will be instructed to take their dose of BDTX-189 with approximately 240 mL water within 
30 minutes after starting the high-fat meal.  On the assigned day of PK assessment in the fasted 
state, BDTX-189 will be administered together with approximately 240 mL water, following an 
overnight fast of at least 10 hours.  Patients should not consume any food for at least 4 hours 
after the dose.  The use of agents that suppress gastric acidity (H2 receptor antagonists, proton 
pump inhibitors, and intraluminal antacids) and agents that delay gastric emptying are prohibited 
from 1 week prior to the Day -4 dose until C1D1, when only proton pump inhibitors will be 
prohibited, as described in Section 4.5.2.  Please see Table 11 (PK Sample Collection Food 
Effect Part A) for specific time points. 
Patients will be given a high-fat breakfast in order to assess food effects on the PK of 
BDTX-189.  An example high-fat breakfast that will be provided is a standard McDonald’s 


 
 
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breakfast, which might include an Egg McMuffin, bacon, hash browns, and milk.  
Note: Alternative food components/quantity and/or time (i.e., lunch) may be allowed as per 
timing of dose administration and as approved by the Investigator/Sponsor.  In addition, a low-
fat breakfast may also be assessed as emerging data dictate.  An example low-fat breakfast may 
include 8 ounces of milk (1% fat), one boiled egg, and one packet flavored instant oatmeal with 
water (approximately 400-500 calories). 
5.3.2. 
Electrocardiogram Measurements 
Single ECGs will be required pre-dose at the time points indicated in the Schedule of 
Assessments (Table 1, Table 2, and Table 3).  Electrocardiograms (single) will be obtained after 
the patient has been resting quietly in semi-supine position for at least 5 minutes before the ECG.  
Electrocardiogram parameters (PR interval, QRS interval, QTcF, and heart rate) will be 
recorded.  When multiple assessments coincide, ECGs will be done immediately before the 
scheduled PK sample or any other blood draw. 
Time-matched triplicate ECG measurements will also be collected for patients in Part A’s Dose 
Escalation and Food-Effect cohorts, and patients who are undergoing detailed PK assessment of 
a smaller and reformulated tablet in the Safety Expansion.  ECG measurements will coincide 
with the detailed PK assessments around the projected Cmax in patients to evaluate any corrected 
QT (QTc) concentration-effect relationship.  These ECG measurements will be performed in 
triplicate pre-dose and at 1.0, 2.0, 3.0, and 4.0 hours post-dose on C1D1 and C1D15 starting with 
dose level 4 (200 mg) and onwards for the QD schedule and starting with dose level 1 for the 
BID dosing schedule, if a more frequent dosing schedule is pursued.  For each set of triplicate 
ECGs, three standard resting 12-lead ECGs will be obtained in close succession and not more 
than 2 minutes apart (4 minutes total for 3 ECGs).  Electrocardiograms will be obtained after the 
patient has been resting quietly in semi-supine position for at least 5 minutes, prior to the first 
ECG procedure and during the triplicate ECG collection. 
Please refer to the Schedule of Assessments (Table 1 and Table 2). 
5.3.3. 
Response Assessments 
Patients will be evaluated for response to treatment after 2 cycles of treatment.  Response will be 
assessed at 6-week intervals (±3 days) during the first 24 weeks (8 cycles) of study treatment.  
Thereafter, patients will be evaluated for response to treatment every 12 weeks (±7 days), at the 
EOT visit (if not performed within the previous 4 weeks), and at the discretion of the 
Investigator.  Patients with PD or unacceptable toxicity should be discontinued from the study; 
patients with SD or response to therapy will continue treatment.  However, patients who are 
receiving clinical benefit in the opinion of the treating Investigator may be allowed to stay on 
study beyond initial radiological progression after consultation with the Medical Monitor if it is 
felt that it is in the patient’s best interest.  The assessments to be performed at this time are 
specified in Appendix B.  All target and non-target lesions documented at screening must be 
assessed.  Please refer to Section 7 for further instructions on evaluating response (e.g., PD, SD). 
The following assessments will be performed if abnormal at baseline or if clinically indicated: 
• CT scan or MRI of chest, abdomen, and pelvis plus any other sites of known disease.   
• CT scan head/MRI brain if history of CNS metastasis.   


 
 
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Investigators must ensure that images of all chest and abdomen CT/MRI scans for patients 
enrolled in Part B are available for transmission to the Sponsor for a future central reading by a 
BICR committee depending on preliminary efficacy results from Part A (see separate imaging 
charter). 
5.3.4. 
Patient Reported Outcomes (Part B only) 
Patient reported outcomes (PROs) will be collected at C1D1, C1D8 and on Day 1 of every Cycle 
C2-C9.  After C9D1 continue to collect electronic patient reported outcomes (ePROs) every 3 
months (±14 days), at the EOT visit, and 30-Day Safety Follow-up visit.  Continue to collect 
ePROs even if the patient has discontinued taking the study drug until subsequent anti-tumor 
therapy is initiated.  PROs should be provided to the patient as soon as they arrive at the site for 
their visit, before any other assessments are performed.   
Table 9 
ePRO Assessments (Part B only) 
Assessments 
NSCLC 
Breast Cancer  
Other Cancers 
NCCN FACT FBSI-16 (16 questions) 
 
X 
 
NCCN-FACT FLSI-17 (17 questions) 
X 
 
 
FACT-G (27 questions)a 
X 
X 
X 
EQ-5D-5L (5 questions) 
X 
X 
X 
Physical Function PROMIS Short Form 
8c (8 questions) 
X 
X 
X 
NCI-CTCAE (14 questions) 
X 
X 
X 
Abbreviations: CTCAE = common terminology criteria for adverse events; ePRO = electronic patient reported 
outcome; EQ-5D-5L = EuroQol Group’s 5-domain 5-level questionnaire; FACT = functional assessment of cancer 
therapy; FACT-G = functional assessment of cancer therapy-general; FBSI = functional Assessment of Cancer 
Therapy Breast Symptom Index; FLSI = Functional Assessment of Cancer Therapy Lung Cancer Symptom Index; 
NCI = national cancer institute; NCCN = national comprehensive cancer network; PROMIS = Patient Reported 
Outcomes Measurement Information System.   
a For Cohorts 1-3: Patients will answer only 13 of the 27 questions in the FACT-G questionnaire.   
 
5.4. 
Follow-up Periods and Study Completion 
5.4.1. 
End-of-Treatment Visit 
The EOT visit will be performed as soon as possible (preferably within 3 days but no later than 
14 days) after permanent discontinuation of the study treatment or when the Investigator decided 
with the patient to permanently discontinue the study treatment or when the Investigator became 
aware that the study treatment had been discontinued.  The assessments of the EOT visit will 
then be performed instead of at the next planned visit.  If the patient finishes treatment without 
having PD, tumor assessment/imaging must be performed at the time of treatment 
discontinuation unless it has been done within the past 4 weeks. 
5.4.2. 
30-day Safety Follow-up Visit 
All patients will be followed during the off-treatment period until all treatment-related toxicity 
has resolved, or for at least 30 days (±3 days) post-study drug discontinuation, or until the start 


 
 
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of another anti-cancer treatment, in which case this visit should occur before the start of 
subsequent therapy.  Any concomitant medications received up to 30 days after the last dose of 
study medication should be recorded.  For Part B and the Safety Expansion portion of Part A 
subsequent anticancer therapy will continue to be collected as outlined in Table 2 and Table 3. 
Thirty-day Safety Follow-up visit assessments do not need to be repeated if a new anti-cancer 
therapy was initiated within 7 days of the EOT visit, unless further study drug was administered 
or there was a new abnormal test result when last assessed (including an abnormal test result 
which had worsened from previous).  If the EOT visit is more than 30 days after the last dose of 
study treatment, the 30-Day Safety Follow-up visit is not required. 
5.4.3. 
Extended Follow-up Period (Safety Expansion and Part B) 
For patients participating in Safety Expansion portion of Part A and all patients in Part B, 
additional follow-up for OS, PFS, and the first subsequent anti-cancer therapy after the 30-Day 
Safety Follow-up visit will be performed every 3 months (±14 days) until 2 years after the first 
study drug dose if the patient has stopped treatment prior to PD based on RECIST Version 1.1 as 
assessed by the Investigator (see Appendix B) or another withdrawal criterion is met: 
• Start of a new anti-cancer therapy.   
• Lost to follow-up.   
• Death.   
• End of the whole study.   
Follow-up information for OS may be obtained by phone. 
5.5. 
Early Patient Termination/Patient Withdrawal 
Patients who discontinue treatment early due to PD, a DLT, or withdrawal will be asked to have 
all EOT safety evaluations performed as described in the protocol (see the Schedule of 
Assessments [Table 1,Table 2, and Table 3]).  If a patient withdraws from treatment during 
Cycle 1 due to any reason other than a DLT and does not meet the minimum requirements for 
inclusion in the DLT-evaluable population described in Section 4.3.3, an additional patient may 
be enrolled to ensure an adequate number of evaluable patients. 
5.6. 
Pharmacokinetic Assessments 
The plasma PK parameters (including AUC0-INF, AUC(0-τ), Cmax, Tmax, t1/2, Cl/F, and Vd/F) of 
BDTX-189 following oral administration will be assessed by analysis of blood plasma samples 
(see Table 10).  Patients participating in the Dose Escalation cohorts during Part A will undergo 
detailed PK evaluation according to Table 10.  Patients participating in the initial Dose 
Escalation where BDTX-189 was evaluated fasting should also take the study drug fasting for 
the detailed PK assessment.  Patients enrolled in cohorts evaluating BDTX-189 in the non-
fasting state should be provided a meal of their choice in connection with the detailed PK 
assessment as instructed in Section 6.1.2. 
All patients enrolling into the Safety Expansion will have blood drawn on Day 1 of Cycles 2, 3, 
4, 5 and every other cycle thereafter for sparse pop PK sampling.  In addition, a minimum of 
12 patients in the Safety Expansion will be administered a smaller and reformulated 200 mg 
tablet and will undergo detailed PK evaluation according to Table 10 on C1D1 and C1D15.  This 
evaluation will be performed at selected study sites capable of performing detailed PK 


 
 
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procedures.  Detailed PK sampling will be collected on Day 15 (i.e., after 14 days of daily 
treatment with the smaller and reformulated 200 mg tablet) of that subsequent cycle according to 
Table 10.   
Table 10 
BDTX-189 pharmacokinetic collection times (Part A Dose Escalation and 
Safety Expansion patients)  
Study Day 
PK draws (hours post-dose)a 
Collection window (± mins) 
C1D1 
pre-dosec 
 
 
0.5 
5 
 
0.75 
5 
 
1c 
10 
 
1.5 
10 
 
2c 
15 
 
3c 
15 
 
4c 
20 
 
6 
30 
 
8d 
30 
 
24e 
30 
C1D15b 
pre-dosec 
 
 
0.5 
5 
 
0.75 
5 
 
1c 
10 
 
1.5 
10 
 
2c 
15 
 
3c 
15 
 
4c 
20 
 
6 
30 
 
8d 
30 
 
24e 
30 
Sparse PK Sampling (Pop PK) 
Cycles 2, 3, 4, 5 and every 
other cycle thereafter (± 2 
days) 
Pre-dose 
1st sample: 0.5 - 1.5 hours post-dosea 
2nd sample: 2 - 4 hours post-dosea 
n/a 
Abbreviations:  C = Cycle; D = Day; mins = minutes; n/a = not applicable; PK = pharmacokinetic. 
a The actual post-dose time of collection should be recorded.   
b Patients in Part A who initiated treatment with the larger 200 mg tablet may be switched to the smaller and 
reformulated 200 mg tablet at the beginning of their subsequent cycles.  Detailed PK sampling will be collected 
on Day 15 (i.e., after 14 days of daily treatment with the smaller 200 mg tablet) of that subsequent cycle.   
c ECG measurements will be performed in triplicate pre-dose and at 1.0, 2.0, 3.0, and 4.0 hours (+/- 5 minutes) 
post-dose on C1D1 and C1D15 starting with dose level 4 (200 mg) and onwards for the QD schedule and starting 
with dose level 1 for the BID dosing schedule.  For each set of triplicate ECGs, 3 standard resting 12-lead ECGs 
will be obtained in close succession and not more than 2 minutes apart (4 minutes total for 3 ECGs); see Section 
5.3.2.   
d Patients on the BID schedule should have their 8-hour PK samples drawn prior to the second dose of the day.   
e The 24-hour sample will be collected prior to the administration of study drug on Day 2 or Day 16, as appropriate. 


 
 
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In Part A, time-matched ECG measurements will be collected coinciding with the detailed PK 
assessments around the projected Cmax in patients to evaluate any QTc concentration-effect 
relationship.  See Table 1, Table 2, and Section 5.3.2 for specific time points. 
For Part B, sparse PK blood samples will be collected at approximately the following time 
points: 
• Cycles 1 to 5 and every other cycle thereafter (± 2 days), Day 1: One pre-dose, two post-
dose blood draws, the 1st draw at 0.5 – 1.5 hours post-dose and the 2nd draw at 2 – 4 hours 
post-dose.   
Note: An ad hoc PK sample should be drawn (whenever possible) in case of a severe adverse 
event or at pre-dose in the event of dose modification, to assess the safety of the patient.   
5.6.1. 
Pharmacokinetic Assessments – Food Effect (Part A) 
Plasma PK parameters (including AUC0-INF, AUC(0-τ), Cmax, Tmax, t1/2 , Cl/F, and Vd/F) of 
BDTX-189 following oral administration in a fed/fasted state will be assessed by analysis of 
blood samples at the time points specified in Table 11. 
 
Table 11 
BDTX-189 pharmacokinetic collection times – Lead-in phase for Food-Effect (Part A) 
Study Day 
PK draws (hours post-dose) 
Collection window (± mins) 
Day -4 
pre-dose 
 
 
0.5 
5 
 
0.75 
5 
 
1 
10 
 
1.5 
10 
 
2 
15 
 
3 
15 
 
4 
20 
 
6 
30 
 
8 
30 
Day -1 
pre-dose 
 
 
0.5 
5 
 
0.75 
5 
 
1 
10 
 
1.5 
10 
 
2 
15 
 
3 
15 
 
4 
20 
 
6 
30 
 
8 
30 
Abbreviations:  mins = minutes; PK = pharmacokinetic.   


 
 
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Note: Beginning with Cycle 1 Day 15, PK sampling will continue as per all other patient cohorts (see Table 10).  
There is no PK sampling on C1D1 for patients in the Food-Effect cohort.   
5.7. 
Biomarker Assessments 
5.7.1. 
Archival Tumor Samples 
Tumor samples will be collected during the screening period for retrospective confirmation of 
allosteric ErbB mutations using a diagnostic test that is being developed.  Archival tumor 
samples or tumor tissue from a new pretreatment biopsy is required for all patients enrolled in 
the Safety Expansion portion of Part A and Part B who have allosteric ErbB mutations.  Archival 
tumor samples or tissue from a new pretreatment biopsy is requested for patients with allosteric 
ErbB mutations enrolled in the Dose Escalation portion of Part A.   
Samples should be provided as a tissue block.  Alternatively, if a tissue block cannot be provided 
12-20 freshly cut formalin-fixed paraffin-embedded (FFPE) unstained slides may be submitted.  
Freshly cut unstained slides are preferred, however unstained slides that were sectioned within 2 
years prior to the patient enrolling in the study may be submitted only if stored in the appropriate 
long-term storage conditions (-80℃).  If the quantity of archival tumor tissue available is 
insufficient to obtain 12-20 unstained slides, a new tumor tissue biopsy sample must be obtained 
prior to starting study treatment.   
Further details on sample processing, handling, and shipment are provided in the Laboratory 
Manual. 
5.7.2. 
Fresh Biopsies 
Patients in the Dose Escalation portion of Part A will be required to undergo baseline and on-
treatment tumor biopsies if the tumor is amenable for biopsy in the opinion of the Investigator.  
For patients participating in the Safety Expansion cohort(s) or any cohort in Part B an archival 
tumor tissue sample is required, if an archival tumor tissue sample is not available, a fresh tumor 
biopsy will be required at baseline. 
In Part A, the on-treatment biopsy is planned to be obtained from dose level 5 (400 mg) or an 
earlier dose cohort (e.g., 200 mg) if emerging data suggest and continue at higher dose levels 
until data supports target engagement in downstream signaling.  Fresh tumor biopsies will be 
collected at baseline (or within 28 days of baseline) and on C2D1 (±5 days).  On C2D1, patients 
must be dosed in the clinic at least 2 hours prior to collecting the biopsy.  The biopsy may be 
collected up to 8 hours after dosing.  Depending on emerging PDx data, the C2D1 biopsy may be 
collected pre-dose in either the BID cohorts or both cohorts.  Pre-dose biopsies may be collected 
12 hours after a BID dose or 24 hours after a QD dose.  This sample will be used to investigate 
changes in pathway signaling and potential mechanisms of resistance (e.g., ERK 
phosphorylation, evidence of alternative pathway activation [e.g., PI3K/AKT], and co-occurring 
genomic alterations).  The material must include both FFPE and fresh frozen tissue.  A minimum 
of 2 and ideally 4 core biopsies should be obtained.  Detailed sample processing, handling, and 
shipment are provided in the Laboratory Manual. 
All patients in Part A and Part B will be asked to undergo an optional on-treatment tumor biopsy 
at the time of disease progression if the tumor is amenable for biopsy in the opinion of the 
Investigator and the patient consents. 


 
 
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Evaluable paired on-treatment samples will be used to evaluate exploratory biomarkers.  Failure 
to obtain a sufficient tumor sample after making best efforts to biopsy the tumor will not be 
considered a protocol deviation.  When feasible, collection of an optional tumor biopsy at relapse 
is encouraged but will not be considered to be a protocol deviation if the patient does not give or 
withdraws consent. 
Biopsies should be obtained through non-significant risk procedures.  Sampling should be 
undertaken by experienced physicians in appropriate settings.  The on-treatment biopsy can be 
omitted if clinically contraindicated or if the risk of the procedure for the individual patient has 
increased to a significant level as determined by the Investigator. 
Instructions regarding sample collection, sample handling/processing, and sample shipping are 
provided in the Laboratory Manual.  This will include instruction regarding study drug 
administration to be done in the clinic at least 2 hours prior to obtaining the tumor biopsy. 
5.7.3. 
Blood Samples for Circulating Tumor DNA (ctDNA)Analysis 
Blood samples will be collected for exploratory analysis of ctDNA mutations to assess 
correlations with disease activity, effects of study drug, and clinical outcomes.  Blood samples 
will be collected from all patients to generate plasma samples and these samples will be used for 
the extraction and analysis of ctDNA.  The samples will be used to explore the relationship 
between changes in biomarkers and response to treatment.  In addition, innate and acquired 
resistance mechanisms may be explored.  Markers tested may include, but will not be limited to, 
allosteric ErbB mutations, resistance mutations (e.g., 
), and alterations in other 
genes involved in
 and 
 signaling.  Similarly, the relationship between other 
blood-borne biomarkers and drug response and/or PD may be explored.  During treatment, 
ctDNA blood samples will be taken at the following time points: 
Part A Dose Escalation (includes Food-Effect Cohort patients) 
• Cycle 1 Day 1: pre-dose.   
• Cycle 2 Day 1: pre-dose.   
• Cycle 3 Day 1: pre-dose.   
• End of study treatment/PD.   
Part A Safety Expansion Cohort(s) 
• Cycle 1 Day 1: pre-dose.   
• Cycle 2 Day 1: pre-dose.   
• Cycle 3 Day 1: pre-dose.   
• Cycle 5 Day 1: pre-dose.   
• End of study treatment/PD (If not collected at the EOT visit, these samples may be 
collected at the 30-Day Safety Follow-up visit as long as no new anticancer therapy has 
commenced).   


 
 
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Part B 
• Screening 
• Cycle 1 Day 1: pre-dose.   
• Cycle 2 Day 1: pre-dose.   
• Cycle 3 Day 1: pre-dose.   
• Cycle 5 Day 1: pre-dose.   
• Cycle 7 Day 1: pre-dose.   
• Cycle 9 Day 1: pre-dose.   
• One pre-dose sample will be collected every 4th cycle (Cycle 13 Day 1, Cycle 17 Day 1, 
Cycle 21 Day 1, etc.).   
• End of study treatment/PD (If not collected at the EOT visit, these samples may be 
collected at the 30-Day Safety Follow-up visit as long as no new anticancer therapy has 
commenced).   
Instructions regarding sample collection, handling/processing, and shipping are provided in the 
Laboratory Manual. 


 
 
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6. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND RISK 
INFORMATION 
6.1. 
BDTX-189 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
BDTX-189 
100 mg and 200 mg tablets 
(A smaller and reformulated 200 mg tablet 
may be administered to some patients in select 
sites during the Safety Expansion of Part A 
and to all patients enrolling onto Part B).   
Black Diamond 
Therapeutics, Inc. 
6.1.1. 
Labeling, Packaging, and Supply 
The Sponsor will supply the BDTX-189 as tablet formulations of 100 and 200 mg.  A smaller 
and reformulated 200 mg tablet may be introduced during the Safety Expansion of Part A to 
select sites, and will also be administered to patients enrolling onto Part B.  Each high density 
polyethylene (HDPE) bottle will contain 30 tablets.  This tablet is a common granulated blend of 
drug substance and pharmacopeial grade excipients compressed into an immediate release form, 
which is half the size of the larger 200 mg tablet provided to patients in the Dose Escalation 
portion of Part A.  The pharmacopeial grade excipients include starch, microcrystalline cellulose, 
croscarmellose sodium, sodium dodecyl sulfate, colloidal silicon dioxide, and magnesium 
stearate. 
Patients in Part A who initiated treatment with the larger 200 mg tablet may be switched to the 
smaller and reformulated 200 mg tablet at the beginning of their subsequent cycles after 
instruction by the Sponsor. 
At each visit, patients will be dispensed sufficient supplies until the next visit.  Study drug 
compliance will be assessed at each patient visit by review of the dosing diary.  The research 
staff will count and document the amount of study drug taken and returned by the patient.  The 
batch number of the study drug dispensed to the patient should be entered on the eCRF, if 
applicable. 
The immediate packaging will contain a statement to conform with FDA Investigational New 
Drug (IND) requirements as follows: “Caution: New Drug - Limited by federal (or United 
States) law to investigational use.” and according to the applicable local laws for labeling the 
investigational products 
All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for BDTX-189 are included on the investigational product label. 
The Sponsor or its representative must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
6.1.2. 
Preparation and Administration of BDTX-189 
BDTX-189 is administered PO.  The study drug will be provided to the sites by the Sponsor. 
The emerging food-effect data suggest a slight to moderate increase in systemic exposure of 
BDTX-189 when administered with a high fat meal.  Therefore, separate cohorts (QD and BID) 


 
 
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at ≥800 mg/day will be evaluated in the fed state, as will the Safety Expansion cohort(s) and 
Part B.  In this case, patients will be instructed not to take study drug on an empty stomach.  
Patients are allowed to take their dose of BDTX-189 with approximately 240 mL water within 
30 minutes of completing a meal. 
Tablets should be swallowed whole (along with up to 240 mL water), not crushed, chewed, or 
dissolved. 
For the QD dosing schedule, patients will self-administer the study drug with approximately 
240 mL water within 30 minutes of completing a meal.  The time of day for administration of 
BDTX-189 should be as consistent as possible.   
For the BID dosing schedule, BDTX-189 should be taken at approximately the same time each 
morning and approximately the same time each evening, approximately 10 hours after the 
morning dose.  Patients will self-administer the study drug with approximately 240 mL water 
within 30 minutes of completing a meal. 
For the Food-Effect Patients, study drug will be self-administered on an empty stomach 
following a fast of approximately 2 hours.  Patients will continue to fast for approximately 
1 hour after the administration of BDTX-189. 
On scheduled PK collection days, C1D1 and C1D15 during Dose Escalation and Safety 
Expansion, the patient should be instructed to wait until he/she arrives at the study center and 
receives instructions from the research staff to take their morning dose of study medication.   
On the scheduled on-treatment tumor biopsy day, the patient in Part A should be instructed to 
wait until he/she arrives at the study center and receives instructions from the research staff to 
take their study medication.  Study drug administration will take place at least 2 hours prior to 
obtaining the tumor biopsy. 
6.1.3. 
Accountability for All Study Drugs 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
study drug supplies at the site. 
All study drug inventories must be made available for inspection by the Sponsor or its 
representative, e.g., Development Innovations, and regulatory agency inspectors upon request. 
Throughout the study and at its completion, Development Innovations Drug Accountability 
Record Form(s) (or an equivalent form) will be completed by the site and sent to the 
Development Innovations Regulatory Department.  Study drug supplies must not be destroyed 
unless prior approval has been granted by the Sponsor or its representative.  Please contact the 
Sponsor or its representative regarding disposal of any study drug. 


 
 
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7. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response and progression will be evaluated in this study using RECIST Version 1.1 (see 
Appendix B).  Lesions are either measurable or non-measurable according to the criteria.  The 
term “evaluable” in reference to measurability will not be used, as it does not provide additional 
meaning or accuracy. 
At screening, tumor assessments should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may be 
involved based on signs and symptoms of individual patients.  These assessments should be 
performed no more than 28 days before the start of study treatment and, ideally, should be 
performed as close as possible to the start of study treatment.  The methods of assessment used at 
screening should be used at each subsequent follow-up assessment. 
Follow-up assessments should be performed every 6 weeks (±3 days) after the start of BDTX-
189 treatment for the first 8 cycles and every 12 weeks (±7 days) thereafter.  Any other sites at 
which new disease is suspected should also be appropriately imaged.  If an unscheduled 
assessment is performed and the patient has not progressed, every attempt should be made to 
perform subsequent assessments at the scheduled visits while the patient remains on study 
treatment. 
Categorization of objective tumor response assessment will be based on the RECIST v1.1 criteria 
for response: CR (complete response), PR (partial response), SD (stable disease), and PD 
(progressive disease). 
If the Investigator is in doubt as to whether progression has occurred, particularly with response 
to non-target lesions (NTLs) or the appearance of a new lesion, it is advisable to continue 
treatment and reassess the patient’s status at the next scheduled assessment or sooner if clinically 
indicated. 
To achieve “unequivocal progression” on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy.  A modest increase in the size of one or more NTLs is usually not sufficient to qualify 
for unequivocal PD status. 


 
 
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8. 
SAFETY REPORTING AND EVALUATION 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs, 
and measurement of protocol-specified hematology, clinical chemistry, and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drug. 
The Principal Investigator is responsible for recognizing and reporting SAEs to the Development 
Innovations Safety Department (see Section 8.2), and the Development Innovations Safety 
Department in turn notifies the Sponsor (see Section 8.2).  It is the Sponsor-designated 3rd party 
agent’s responsibility to report relevant SAEs to the applicable local, national, or international 
regulatory bodies.  In addition, Investigators must report SAEs and follow-up information to 
their responsible IRBs according to the policies of each IRB. 
The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 
8.1. 
Definitions 
8.1.1. 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the 
use of a drug, without any judgment about causality.  An AE can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including overdose. 
8.1.2. 
Serious Adverse Events 
An AE or a suspected adverse reaction (SAR) is considered “serious” if it results in any of the 
following outcomes: 
• Death.   
• A life-threatening AE.   
• Inpatient hospitalization or prolongation of existing hospitalization.   
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.   
• A congenital anomaly/birth defect.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  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 hospitalization, or development of drug dependency or drug 
abuse. 
It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 


 
 
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necessarily be considered “serious.”  Seriousness serves as the guide for defining regulatory 
reporting obligations and is based on patient/event outcome or action usually associated with 
events that pose a threat to a patient’s life or vital functions.  For example, nausea that persists 
for several hours may be considered “severe” nausea but may not be considered an SAE.  On the 
other hand, a stroke which results in only a limited degree of disability may be considered only a 
mild stroke but would be considered an SAE.  “Severity” and “seriousness” should be 
independently assessed when recording an AE on the eCRF. 
8.1.3. 
Adverse Event Severity 
The severity refers to the intensity of an AE, which is different from seriousness as described in 
Section 8.1.2.  Adverse event severity will be reported at the highest experienced as described in 
Section 8.1.5.  Adverse events severity will be graded according to NCI CTCAE v 5.0.  Events 
not listed in NCI CTCAE will be graded according to the criteria described in Appendix J. 
8.1.4. 
Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE.  “Reasonable possibility” means that there is evidence to suggest a 
causal relationship between the drug and the AE. 
8.1.5. 
Recording and Reporting of Adverse Events 
Recording of Adverse Events 
All AEs of any patient during the course of the research study will be recorded in the eCRF, and 
the Investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration). 
All AEs should be documented in the eCRF.  A description of the event, including its date of 
onset and resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to 
study treatment), and its outcome should be provided, along with the Investigator’s assessment 
of causality (i.e., the relationship to the study treatment).  For an AE to be a suspected treatment-
related event, there should be at least a reasonable possibility of a causal relationship between the 
protocol treatment and the AE.  Adverse events will be graded according to the NCI CTCAE 
Version 5.0, and changes in severity will be documented by recording the AE as separate entries. 
If the AE is serious, it should be reported within 24 hours of the Investigator site awareness or 
receipt of the initial SAE or any follow-up information to Development Innovations Safety 
Department.  Other untoward events occurring in the framework of a clinical study are to be 
recorded as AEs (i.e., AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention, including invasive procedures such as biopsies, medication 
washout, or no treatment run-in). 
Test findings will be reported as an AE if the test result requires an adjustment in the study drug 
or discontinuation of treatment and/or test findings require additional testing or surgical 
intervention, a test result, or finding is associated with accompanying symptoms, or a test result 
is considered to be an AE by the Investigator. 


 
 
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Reporting Period for Adverse Events 
All AEs, regardless of seriousness or relationship to study treatment, spanning from the signing 
of the ICF until 30 calendar days after discontinuation or completion of study treatment as 
defined by the study for that patient after his/her last dose of BDTX-189, are to be recorded on 
the AE page in the eCRF.  The AEs occurring from the signing of the ICF until the first dosing 
with BDTX-189 will be the pre-treatment AEs.  The AEs occurring at or after the first dosing 
will be the TEAEs. 
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the Investigator, the AE or laboratory abnormality/ies is/are 
not likely to improve because of the underlying disease.  In this case, the Investigator must 
record his or her reasoning for this decision in the patient’s medical record. 
Only drug-related SAEs that emerge 30 days or more after the last dose of study medication, as 
well as deaths assessed by the Investigator as treatment-related are to be reported. 
8.1.6. 
Assessment of Adverse Events 
All AEs (regardless of seriousness) whether volunteered by the patient, discovered by study 
personnel during questioning, or detected through physical examination, laboratory tests, or other 
means will be reported appropriately.  Each reported AE will be described by its duration (i.e., 
start and end dates), regulatory seriousness criteria, suspected relationship to the study drug (see 
following guidance), and actions taken. 
To ensure consistency of AE causality assessments, Investigators should apply the following 
general guideline: 
YES:  There is a plausible temporal relationship between the onset of the AE and 
administration of the study treatment, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the study drug; and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 
NO:  Evidence exists that the AE has an etiology other than the study drug (e.g., 
pre-existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to study drug 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
8.2. 
Serious Adverse Event Reporting by the Investigator 
Adverse events classified by the treating Investigator as “serious” require expeditious handling 
and reporting to the Sponsor or designee in order to comply with regulatory requirements.  
Determination of “life-threatening” or “serious” is based on the opinion of either the Sponsor or 
the Investigator. 
Serious AEs occurring at any time from the signing of the ICF through the 30-day follow-up 
period after the last dose of study drug must be reported as SAEs in the eCRF and followed until 
resolution (with autopsy report if applicable).  The Development Innovations Safety 


 
 
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Department must be notified of all SAEs, regardless of causality, within 24 hours of the 
first knowledge of the event by the treating physician or research personnel via the paper 
SAE reporting form. 
Paper SAE Report Forms will be submitted via fax or e-mail using the following contact 
information (during both business and non-business hours): 
 
Safety Dept. Phone#     
 
Safety Dept. Fax #:      
 
Safety Dept. Email:     
 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the Development Innovations Safety Department as soon as it is available.  
The detailed SAE reporting process will be provided to the sites in the SAE reporting guidelines 
contained in the study reference manual. 
8.2.1. 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Principal Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (AE eCRF or paper SAE Report Form).  If a diagnosis is subsequently 
established, it should be reported as follow-up information is available.  If a diagnosis is 
determined subsequent to the reporting of the constellation of symptoms, the signs/symptoms 
should be updated to reflect the diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
methods (e.g., as per RECIST criteria for solid tumors; see Appendix B), should not be reported 
as an SAE. 
8.2.2. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  A persistent AE should only be recorded once (i.e., a single AE) on the AE eCRF.  
If a persistent AE becomes more severe or lessens in severity, the event should be recorded as a 
separate AE.  Each AE must have its own severity grade and corresponding start and stop dates.  
Persistent toxicity from a prior therapy should be recorded as medical history on the medical 
history page on the eCRF.  If this toxicity has increased in severity during the study, this toxicity 
should be recorded as an AE on the AE eCRF with the new severity; the start date for this event 
should be the date when the new severity is observed. 
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  In this case, each occurrence should be recorded as a separate AE with 
corresponding start and stop dates. 


 
 
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8.2.3. 
Abnormal Laboratory or Vital Sign Values 
Abnormal laboratory values will be reported as an AE if the laboratory result requires an 
adjustment in the study drug or discontinuation of treatment, and/or laboratory findings require 
additional testing or surgical intervention, a laboratory result or finding is associated with 
accompanying symptoms, or a laboratory result is considered to be an AE by the Investigator. 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the signs or symptoms should be reported as an AE or SAE, and the associated laboratory value 
or vital sign should be considered additional information that must be collected on the relevant 
eCRF (e.g., laboratory eCRF or vital sign page).  If the laboratory abnormality is a sign of a 
disease or syndrome, only the diagnosis needs to be recorded as an AE on the AE eCRF.   
8.2.4. 
Hy’s Law 
The Investigator is responsible for determining whether a patient meets potential Hy’s Law 
criteria at any time during the study.  Potential Hy’s Law criteria are defined as AST or ALT 
≥3 × ULN together with total bilirubin ≥2 × ULN without initial findings of cholestasis 
(elevation of ALP) at any point during the study following the start of study medication without 
other reason that can explain the combined ALT/AST and bilirubin elevation (e.g. viral hepatitis 
or underlying liver disease). 
When a case meeting potential Hy’s Law is identified, the Investigator will immediately notify 
the Sponsor.  The Investigator will also request a new blood draw to repeat the test immediately 
and will review all previous laboratory data to determine whether potential Hy’s Law criteria 
were met at any study visit prior to or after starting study treatment. 
The Investigator will review the case with the Medical Monitor and agree on the approach for the 
patients’ follow-up assessments, which include monitoring the patient until liver chemistry tests 
and clinical signs and symptoms return to normal or baseline levels, and investigating the 
etiology of the event including diagnostic tests, as appropriate.  The SRC or DMC and other 
subject matter experts may also be involved in the case review and assessment, as needed.  The 
Investigator and Medical Monitor will meet periodically to review all available and emerging 
data and agree upon whether there is an alternative explanation for meeting potential Hy’s Law 
criteria other than drug induced liver injury caused by the study drug.   
Standard safety reporting procedures will be followed for reporting AEs and SAEs according to 
the outcome of the review and assessment.  If it is agreed that there is no alternative explanation 
that would explain the ALT or AST and total bilirubin elevations other than the study drug, then 
the Investigator is required to report an SAE with the term Drug-Induced Liver Injury and the 
causality assessment of “related.” 
Any potential Hy’s Law case should be handled as a serious unexpected adverse event associated 
with the use of the drug and reported to the FDA promptly (i.e., even before all other possible 
causes of liver injury have been excluded).  It should be promptly reported to the FDA before 
fully working up the patient to rule out other etiologies. 
8.2.5. 
Deaths 
Deaths occurring during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to the progression of disease will be recorded on the “End of Study” eCRF.  


 
 
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All other on-study deaths, regardless of attribution, will be recorded on the SAE paper report 
form and expeditiously reported to the Development Innovations Safety Department. 
When recording an SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the AE 
eCRF.  If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “death, cause unknown” on the Adverse Event eCRF.  During post-study survival follow-
up, deaths attributed to progression of disease will be recorded on the “Follow-up Summary” and 
“Death Page” eCRFs. 
8.2.6. 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency department or emergency room.   
• Outpatient or same-day surgery units.   
• Observation or short-stay unit.   
• Rehabilitation facility.   
• Hospice or skilled nursing facility.   
• Nursing homes, custodial care, or respite care facility.   
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study) does not require reporting as an SAE. 
8.2.7. 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History of the eCRF.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an AE eCRF, it is important 
to convey the concept that the pre-existing condition has changed by including applicable 
descriptors, such as new start date, new severity/frequency, etc. 
8.2.8. 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria (see Section 8.1.2).  New primary cancers are those that are 
not the primary reason for the administration of the study treatment and have developed after the 
inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be PD (see Section 8.2.1). 


 
 
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8.2.9. 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a paper report 
form, not available within the eCRF) should be completed and faxed to the Development 
Innovations Safety Department.  The Development Innovations Safety Department should be 
notified expeditiously, irrespective of whether or not it meets the criteria for expedited reporting.  
Abortions (spontaneous, accidental, or therapeutic) must also be reported to the Development 
Innovations Safety Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the Development Innovations Safety Department 
immediately.  Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
A pregnancy itself is not an AE; however, congenital anomalies/birth defects always meet SAE 
criteria and should therefore be expeditiously reported as an SAE using the previously described 
process for SAE reporting.  A Pregnancy Form should also have been previously completed and 
will need to be updated to reflect the outcome of the pregnancy. 
8.2.10. 
BDTX-189 Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF system.  Any 
accidental or intentional overdose with the study treatment that is symptomatic, even if not 
fulfilling a seriousness criterion, is to be reported to the Development Innovations Safety 
Department no greater than 24 hours from first knowledge of the event following the same 
process described for SAE reporting (see Section 8.2). 
8.3. 
Sponsor Serious Adverse Event Reporting Requirements 
Per regulatory requirements, if an SAE is required to be submitted to a regulatory authority, the 
Sponsor or Sponsor-designated third party agent will report it to the competent authority and the 
Investigators/site, and a copy of the report will be submitted to the respective IRB or IEC in 
accordance with ICH guidelines, Directive 2001/20/EC, 21CFR312.32 and other local regulatory 
requirements.   
8.3.1. 
Sponsor Assessment of Expectedness 
The Sponsor and/or Development Innovations Safety Department is responsible for assessing an 
AE or suspected AE for expectedness. 
An SAE or SAR is considered “unexpected” when the following conditions occur: 
• Event(s) is not mentioned in the IB, Reference Safety Information Section 7.12.   
• Event(s) is not listed at the specificity or severity that has been observed.   
This includes SAEs or SARs that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have not previously been 
observed under investigation 
Known as suspected unexpected serious adverse reactions (SUSARs), these events suspected (by 
the Investigator or Sponsor) to be related to the study drug are unexpected (not listed in the IB’s 
Reference Safety Information Section 7.12), are serious (as defined by the protocol), and require 


 
 
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expedient submission to relevant health authorities, ECs, Investigators, and sites within 7 days 
(for fatal or life-threatening events) or 15 days (for all serious events), or as defined by law.  The 
term SUSAR is used primarily in the reporting of events to regulatory authorities. 
Expected SAEs are those events that are listed or characterized in the current IB (Section 7.12).  
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g. summary or listing of SAEs) from the Sponsor will file it along with the 
IB and will notify the IRB/IEC, if appropriate according to local requirements. 


 
 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Design 
This is a Phase 1/2, open-label, 2-part, multi-center study of BDTX-189.  Part A is designed 
primarily to determine the RP2D and dosing schedule, and to characterize the safety, tolerability, 
PK profile, preliminary antitumor activity, and effect of food on BDTX-189 PK. 
Part B is an open label, multi-center, Phase 2 basket study to investigate the antitumor activity of 
BDTX-189 as a single oral agent in patients with a tumor harboring an eligible allosteric ErbB 
mutation. 
Each part will be analyzed and summarized separately.  Descriptive statistics will be used to 
summarize the study data overall and by dose level cohort for Part A unless otherwise specified. 
Additional details on statistical design and evaluation of specific endpoint variables are provided 
in the Statistical Analysis Plan (SAP). 
9.2. 
Estimands 
The primary estimand for Part A is the rate at which DLTs occur after treatment with BDTX-189 
when administered either QD or BID.  It is further described by the following attributes:  
• Population: Patients with advanced solid malignancies as reflected by the 
inclusion/exclusion criteria outlined in Sections 3.1 and 3.2.   
• Variable: DLTs, as defined in Section 4.3.2, occurring during the first 21 days of 
treatment (i.e., Cycle 1).   
• Population-level summary: DLT rate, which is defined as the proportion of patients who 
experience a DLT during Cycle 1.  Separate summaries will be estimated for each 
evaluated dose level of BDTX-189.   
• Intercurrent events: Estimation will be based on the hypothetical situation that all patients 
either receive at least 75% of their planned doses of BDTX-189 during their first 21 days 
of treatment or experience a DLT during their first 21 days of treatment (i.e. are 
considered DLT-evaluable).  Patients who are DLT-evaluable will be included in the 
calculation of the DLT rate.  Additional patients will be enrolled, if necessary, to ensure 
an adequate number of DLT-evaluable patients.   
The primary estimand for Part B is the effect of BDTX-189, when administered at the RP2D, on 
objective response rate as assessed by BICR and per RECIST v1.1.  It is described by the 
following attributes: 
• Population: Patients with solid tumors containing mutations falling into one of the MTC-
A through MTC-G groupings as reflected by the inclusion/exclusion criteria outlined in 
Sections 3.1 and 3.2.   
• Variable: Objective responses defined as CR or PR as assessed by BICR and per RECIST 
v1.1, which occur from the date of first dose of study treatment until the date of the first 
documentation of PD, death or start of new anti-cancer therapy.  Objective responses 
must be confirmed by repeat assessments performed at least 4 weeks later.   


 
 
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• Population-level summary: Objective response rate, defined as the proportion of patients 
in the analysis population with an objective response.  Separate summaries will be 
estimated for various combinations of MTC groupings and tumor types.   
• Intercurrent events: Estimation will be based on a “while on treatment” strategy.  Patients 
who do not have a post-baseline tumor assessment or patients who receive subsequent 
anti-cancer therapies, have PD, die, or otherwise stop tumor assessments prior to 
experiencing a CR or PR will be considered non-responders.   
9.3. 
Sample Size Considerations 
9.3.1. 
Phase 1 (Part A) 
The Phase 1 dose-escalation portion of the study will utilize a BOIN design as described in 
Section 4.3.1 and Appendix G.  Part A will enroll approximately 36 DLT-evaluable patients to 
the QD schedule, and approximately 24 additional DLT-evaluable patients may be treated in the 
dose-escalation portion to assess the BID schedule.  The number of DLT-evaluable patients in 
Part A will not exceed 60, excluding patients in the accelerated titration step.  Because both a 
QD and BID schedule are being evaluated and one RP2D and schedule will be selected, the 
Safety Expansion cohort(s) will include up to 48 patients, including a minimum of 12 patients for 
PK evaluation of a smaller and reformulated 200 mg tablet.  In addition, up to 16 PK-evaluable 
patients will be enrolled to evaluate food-effect for a total of up to approximately 128 evaluable 
patients in Part A.  The final sample size will depend on the dosing schedule, the number of 
DLTs, and the total number of cohorts treated before a DLT is observed and the MTD is 
determined. 
9.3.2. 
Phase 2 (Part B) 
For Cohorts 1, 2, and 5, the sample size was determined for each cohort independently.  For 
Cohorts 3 and 4, the sample size was determined for each subgroup within a cohort 
independently. 
The rationale for the different null hypotheses and target ORR values for each cohort/subgroup is 
discussed in Section 4.2. 
Sample sizes for Cohorts 1-5 were estimated using nQuery version 8.6.  The following sections 
provide the details of sample size considerations for each cohort and a summary of sample size 
for each cohort for various scenarios. 
9.3.2.1. 
Sample Size Considerations for Cohorts 1 and 2 
The sample size in each cohort will be based on a Simon 2-stage optimal design (Simon 1989), 
with the modification of adding an additional earlier assessment of futility.  Therefore, Cohorts 1 
and 2 will be evaluated in 3 stages.   
Each cohort is designed to provide approximately 80% power to detect a true target ORR of 
30%, while rejecting a null ORR of 17.5% at a nominal 1-sided alpha level of 0.05.  For each 
cohort, 15 patients will initially be enrolled.  If no patient has an objective response at the end of 
Stage 1, enrollment to the cohort will stop, otherwise an additional 16 patients will be enrolled.  
If 6 or fewer of the 31 total patients have objective responses at the end of Stage 2, enrollment to 


 
 
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the cohort will stop, otherwise an additional 54 patients will be enrolled.  The null hypothesis 
will be rejected if at least 21 of the 85 total patients have objective responses.   
A small number of first-line NSCLC patients may be enrolled to Cohort 1, in which case, these 
patients will be analyzed separately and will not count towards the numbers of patients described 
above.   
Table 12 provides the operating characteristics for Cohorts 1 and 2. 
Table 12 
Operating Characteristics for Cohorts 1 and 2 
 
Cumulative Probability of Stopping for Futility 
(Number of Responders/Total N)1 
 
 
 
Stage 1 
(0/15) 
Stage 2  
(≤ 6/31) 
Stage 3 
(≤ 20/85) 
True ORR = 17.5% 
0.0558 
0.7081 
0.9541 
Overall Type I Error: 0.0459 
True ORR = 30% 
0.0047 
0.1355 
0.1992 
Overall Type II Error: 0.1992 
1 Based on exact binomial distribution. 
9.3.2.2. 
Sample Size Consideration for Cohort 3 
Cohort 3 will include 5 distinct mutational type subgroups (MTC-B, MTC-C, MTC-D, MTC-E 
and MTC-F) with each being evaluated independently.  
The sample size in each subgroup will be based on a Simon 2-stage optimal design (Simon 
1989).  Each subgroup is designed to provide approximately 80% power to detect a true target 
ORR of 20%, while rejecting a null ORR of 5% at a nominal 1-sided alpha level of 0.05.  For 
each subgroup, 10 patients will initially be enrolled.  If no patient has an objective response at 
the end of Stage 1, enrollment to the subgroup will stop, otherwise an additional 19 patients will 
be enrolled.  The null hypothesis will be rejected if at least 4 of the 29 total patients have 
objective responses.   
Table 13 provides the operating characteristics for each Cohort 3 subgroup. 
Table 13 
Operating Characteristics for Cohort 3 
 
Cumulative Probability of Stopping for Futility 
(Number of Responders/Total N)1 
 
Stage 1  
(0/10) 
Stage 2  
(≤3/29) 
True ORR = 5% 
0.5987 
0.9532 
Overall Type I Error: 0.0468 
True ORR = 20% 
0.1074 
0.1989 
Overall Type II Error: 0.1989 
 1 Based on exact binomial distribution.  
9.3.2.3. 
Sample Size Considerations for Cohort 4 
Cohort 4 will include patients from 3 distinct cancer-type subgroups (NSCLC, biliary or cervical 
cancer), with each being evaluated independently.   
The sample size in each subgroup will be based on a Simon 2-stage optimal design (Simon 
1989).  Each subgroup is designed to provide approximately 80% power to detect a true target 
ORR of 20%, while rejecting a null ORR of 5% at a nominal 1-sided alpha level of 0.05.  For 
each subgroup, 10 patients will initially be enrolled.  If no patient has an objective response, 


 
 
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enrollment to the subgroup will stop, otherwise an additional 19 patients will be enrolled.  The 
null hypothesis will be rejected if at least 4 of the 29 total patients have objective responses.   
Table 14 provides the operating characteristics for each Cohort 4 subgroup. 
Table 14 
Operating Characteristics for Cohort 4 
 
Cumulative Probability of Stopping for Futility 
(Number of Responders/Total N)1 
 
Stage 1  
(0/10) 
Stage 2  
(≤3/29) 
True ORR = 5% 
0.5987 
0.9532 
Overall Type I Error: 0.0468 
True ORR = 20% 
0.1074 
0.1989 
Overall Type II Error: 0.1989 
 1 Based on exact binomial distribution. 
9.3.2.4. 
Sample Size Considerations for Cohort 5 
Cohort 5 will have a heterogeneous patient population with many cancer types and MTC subsets.  
This cohort will include all eligible patients who cannot be assigned to Cohorts 1-4.   
The sample size will be based on a Simon 2-stage optimal design (Simon 1989).  The cohort is 
designed to provide approximately 80% power to detect a true target ORR of 20%, while 
rejecting a null ORR of 10% at a nominal 1-sided alpha level of 0.05.  Thirty patients will 
initially be enrolled.  If 3 or fewer patients have an objective response, enrollment to the cohort 
will stop, otherwise an additional 59 patients will be enrolled.  The null hypothesis will be 
rejected if at least 14 of the 89 total patients have objective responses.  
Table 15 provides the operating characteristics for Cohort 5. 
Table 15 
Operating Characteristics for Cohort 5 
 
Cumulative Probability of Stopping for Futility 
(Number of Responders/Total N)1 
 
Stage 1  
(≤3/30) 
Stage 2  
(≤13/89) 
True ORR = 10% 
0.6474 
0.9522 
Overall Type I Error: 0.0478 
True ORR = 20% 
0.1227 
0.1982 
Overall Type II Error: 0.1982 
1 Based on exact binomial distribution. 
9.4. 
Analysis Population 
The following analysis populations will be used: 
• The Intent-To-Treat (ITT) population is defined as all patients who signed informed 
consent.  The ITT population is the primary population for the summarization of 
enrollment.   
• The Full Analysis (FA) population is defined as all patients who receive at least one dose 
of BDTX-189.  The FA population is the primary population for both safety and Part A 
efficacy analyses.   
• The Per-Protocol Efficacy (PPE) population is defined as all FA population patients who 
meet the eligibility criteria, receive BDTX-189, and have at least one baseline and post-
baseline response assessment.  The PPE population will be used for exploratory 
sensitivity analyses.   


 
 
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• The DLT-evaluable population will consist of all patients in Part A (excluding those 
patients in the Food-Effect Cohort) who receive at least 75% of the planned oral doses 
during Cycle 1 and complete all required safety evaluations or who have a DLT in Cycle 
1.   
• The Pharmacokinetic (PK) population is defined as all patients who receive at least one 
dose of BDTX-189 and have at least one post-dose PK blood collection with associated 
bioanalytical results.   
• The Pharmacodynamic (PDx) population is defined as all patients who receive at least 
one dose of BDTX-189 and have post-baseline ctDNA samples or have paired 
on-treatment tumor tissue biopsy results.   
9.5. 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations, and range for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented.  Time to event endpoints will be reported using Kaplan-Meier 
estimates, with approximate 2-sided 95% confidence intervals (CIs) for median time to event.   
9.5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized descriptively.  Data to be 
tabulated will include demographic features such as age, sex, and race, as well as disease-
specific characteristics.   
The number and percentages of patients who were screened, registered, and treated; who 
completed the treatment/study; and who were withdrawn from treatment/study for any reasons 
will be presented overall and by treatment cohort for Part A and Part B.   
9.5.2. 
Hypotheses to be Tested 
Part B Cohorts 1 and 2 of the study are designed to test the null hypothesis that the true ORR of 
BDTX-189 is less than or equal to 17.5%, while having sufficient power to detect (i.e., reject the 
null hypothesis with) a true ORR of 30%.   
Part B Cohorts 3-4 of the study are designed to test the null hypothesis that the true ORR of 
BDTX-189 is less than or equal to 5%, while having sufficient power to detect a true ORR of 
20%.   
Part B Cohort 5 of the study is designed to test the null hypothesis that the true ORR of BDTX-
189 is less than or equal to 10%, while having sufficient power to detect a true ORR of 20%.   
9.5.3. 
Efficacy Analysis 
The Investigator-assessed objective response is a secondary endpoint for Part A. BICR-assessed 
objective response is a primary endpoint for Part B.  Secondary objectives of Part B include 
evaluating the Investigator-assessed objective response, and evaluating both the Investigator and 
BICR-assessed duration of response (DOR), disease control rate (DCR), and PFS as evidence of 
the antitumor activity of BDTX-189.  Evidence of antitumor activity for ORR, DOR, DCR, and 
PFS will be determined by RECIST v1.1.  OS is also a secondary endpoint for Part B. 




 
 
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9.5.5. 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of TEAEs.  Treatment 
emergent AEs are those with an onset on or after the initiation of therapy (on or after C1D1, first 
dose of study drug) and will be graded according to NCI CTCAE Version 5.0. 
The TEAEs will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA; https://www.meddra.org/about-meddra/) and summarized using system 
organ class and preferred term for all patients in the FA population.  In addition, summaries of 
SAEs, TEAEs leading to treatment discontinuation, TEAEs by maximum NCI CTCAE grade, 
and TEAEs related to study treatment will also be presented.  TEAEs will be summarized 
separately for Part A and Part B.  In Part A, the TEAE summary will be provided by dose level, 
cohort, and overall, whereas in Part B, the TEAE summary will be provided by cohort, 
subgroups within a cohort (as appropriate), and overall.  Additional TEAE analysis (such as 
subset or pooled analysis) could be performed if data warrants. 
Other safety endpoints including laboratory results, vital signs, physical examinations, ECG 
findings, and cardiac function will be summarized for all patients in the FA population and 
presented separately for Parts A and B, respectively.  Descriptive summary statistics of observed 
values, as well as changes from baseline, will be presented.  In addition, laboratory parameters 
will also be summarized by shift from baseline CTCAE grade to maximum post-baseline 
CTCAE grade (NCI CTCAE Version 5.0). 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO DD; https://www.who-umc.org/) and they will be listed and summarized for Part A and 
Part B separately. 
9.5.6. 
Pharmacokinetics 
Plasma concentrations of BDTX-189 will be used to calculate the PK parameters.  The plasma 
PK parameters to be analyzed include AUC0-INF, AUC(0-τ), Cmax, Tmax, and t1/2.  These parameters 
will be listed by individual patient and summarized by descriptive statistics (means, medians, 
ranges, standard deviations, geometric means, 90% CI, and coefficients of variation) as 
appropriate, by treatment group/cohort.  Pharmacokinetic parameters will be analyzed separately 
for Dose Escalation and the Food-Effect Cohort. 
For the Food-Effect Cohort, the following exposure measures and PK parameters will be derived 
and reported:  AUC0-INF, AUC0-t, Cmax, Tmax, tlag, t1/2, Cl/F, and Vd/F.  Individual patient 
measurements as well as summary statistics (e.g., group averages, standard deviation, 
coefficients of variation, ranges) will be reported.  Exposure measurements (AUC and Cmax) will 
be log-transformed.  When the 90% CI for the ratio of the log-transformed population geometric 
means of either AUC0-INF (AUC0-t when appropriate) or Cmax between fed and fasted treatments 
fails to meet the limits of 80 – 125%, specific recommendation on the clinical significance of the 
food effect will be provided.  The clinical relevance of any difference in Tmax and tlag will be 
described. 
Population PK parameters including CL/F, Vd/F, and Ka will also be used to investigate the PK 
of BDTX-189 in Part B.  Oral clearance will be used to generate estimates of BDTX-189 AUC. 
Further details on the PK analyses will be documented in a separate PK analysis plan. 




 
 
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10. 
QUALITY ASSURANCE AND QUALITY CONTROL 
10.1. 
Monitoring 
Site monitoring shall be conducted to ensure that patient protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, Good Clinical Practice (GCP), ICH and, when appropriate, regulatory 
guidelines. 
10.2. 
Audits and Inspections 
The Investigator will permit study-related quality audits and inspections by Development 
Innovations or its representative(s), government regulatory authorities, and the IRB(s) of all 
study-related documents (e.g., source documents, regulatory documents, data collection 
instruments, case report forms).  The Investigator will ensure the capability for review of 
applicable study-related facilities.  The Investigator will ensure that the auditor or inspector or 
any other compliance or Quality Assurance reviewer is given access to all study-related 
documents and study-related facilities. 
At the discretion of the Sponsor or its delegate, Source Document Verification may be performed 
on partial or all data items as defined in study documents and/or plans. 
Participation as an Investigator in this study implies the acceptance of potential inspection by the 
Sponsor or its representative, government regulatory authorities, and IRB(s)/IEC(s). 
10.3. 
Study Committees 
10.3.1. 
Safety Review Committee (Part A Only) 
During Part A of the study, dose Escalation decisions (as per the BOIN criteria described in 
Section 4.3.1 and Appendix H) and determination of the RP2D and/or MTD will be evaluated by 
the SRC and based upon review of all safety data that occur during the first cycle of therapy 
(21 days), as well as longer term safety data, as appropriate.  The SRC will convene 
approximately once monthly when there are at least 1 to 3 evaluable patients at a dose level who 
have completed Cycle 1 to evaluate all available safety information (including AEs and 
laboratory abnormalities that are not DLTs), as well as available PK and PDx information.  
When other patients are ongoing at the time of this review, the SRC may decide to defer their 
decision until these further data become evaluable. 
Any patient started on treatment in error because he or she failed to comply with all of the 
selection criteria but who otherwise meets the criteria of an evaluable patient will be reviewed on 
a case-by-case basis by the SRC to determine if the patient should be included or excluded in the 
decision for Dose Escalation. 
The SRC will make decisions with regard to escalation/de-escalation to the next planned dose or 
to an intermediate dose level, expand cohorts (including the Food-Effect cohort and BID 
schedule cohorts) to the maximum allowed, or make the decision to stop recruitment to the Dose 
Escalation part of the study for one or both schedules, as applicable, after review of the data from 
all cohorts.  The decisions and decision-making of the SRC on the next dose level will be 
documented and provided to the Investigators prior to dosing any new patients. 


 
 
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Membership of the SRC will include: 
• Principal Investigator from each of the investigational sites, or a medically qualified 
delegate from each of the investigational sites.   
• Medical Safety Team representative from Sarah Cannon Development Innovations.   
• Sponsor Chief Medical Officer or designee.   
• Sponsor Medical Monitor.   
• Sponsor Study Statistician.   
• Sponsor pharmacology scientist and other technical experts, as appropriate.   
10.3.2. 
Data Monitoring Committee (Part B Only) 
To provide independent oversight of safety and efficacy, a data monitoring committee (DMC) 
will be instituted.  The DMC will meet regularly to ensure that patient safety is carefully 
monitored.  The DMC will convene to review relevant data determine if each stage can proceed 
to the next based on the futility boundaries for each cohort as described in Section 9.3.2.  The 
DMC will convene additional ad hoc meetings if necessary.  Following each meeting, the DMC 
will recommend continuation, modification, or discontinuation of each cohort and/or subgroup.  
A separate DMC charter will describe the activities of this committee in more detail.   
10.3.3. 
Blinded Independent Central Review Committee 
A blinded independent central review (BICR) committee will review all available tumor 
assessment scans for patients enrolled to Part B of this study.  Each image will be independently 
reviewed.  The process for review and adjudication of the images will be provided in the imaging 
review charter (IRC).   
10.3.4. 
Protocol Steering Committee 
The role of the Steering Committee is to provide scientific oversight of the conduct of the study.  
This includes oversight of the practical aspects of the study as well as ensuring that the study 
continues to be run in a way to ensure the study objectives can be assessed. 
Specific responsibilities of the Steering Committee include, but are not limited to, the following: 
• Provide overall scientific supervision of the study.   
• Take steps to reduce deviations from the protocol to a minimum.   
• Periodic review of the progress of the study.   
• Review and discuss emerging scientific data which may impact the ongoing study and 
make recommendations to the Sponsor.   


 
 
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11. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of GCP outlined in the ICH E6 
Tripartite Guideline and Code of Federal Regulations (CFR) Title 21 part 312, applicable 
government regulations, institutional research policies and procedures, and any other local 
applicable regulatory requirement(s). 
11.1. 
Institutional Review Board Approval 
The clinical study protocol, ICF, IB, available safety information, patient documents (e.g., study 
diary), patient recruitment procedures (e.g., advertisements), information about payments (i.e., 
Principal Investigator payments) and compensation available to the patients, and documentation 
evidencing the Principal Investigator’s qualifications should be submitted to the IRB for ethical 
review and approval, if required by local regulations, prior to the study start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit to and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the ICF.  Investigators will be advised by the 
Sponsor or designee whether an amendment is considered substantial or non-substantial and 
whether it requires submission for approval or notification only to an IRB. 
Safety updates for BDTX-189 will be prepared by the Sponsor or its representative as required, 
for distribution to the Investigator(s) and submission to the relevant IRB. 
11.2. 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
For European Union (EU) Only:  If applicable, the Principal Investigator will notify the IEC 
within 90 days of the end of the study (as defined in Section 4.4).  If the study terminates early, 
the Principal Investigator must notify the IEC within 15 days of the termination.  A reason for 
the early termination must be provided (as defined in Directive 2001/20/EC). 
11.3. 
Study Registration 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks, and 
discomforts.  Human protection committee (Institutional Review Board/Independent Ethics 
Committee [IRB/IEC]) approval of this protocol and any associated informed consent forms 
(ICFs) is required.  Eligible patients who wish to participate in the study will be enrolled in the 
study. 
Registration must occur prior to the initiation of protocol-related procedures and therapy.  Patient 
registration and dose level assignment will be performed by Sarah Cannon Development 
Innovations (Development Innovations).  The Development Innovations designee will document 
the patient identification number, dose level (Part A) or cohort number (Part B), and date of 
enrollment on the registration form and in the electronic data capturing (EDC) system and will 


 
 
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send the completed form back to the site as soon as possible, but no later than 24 hours following 
the registration request. 
For additional information regarding study registration, please refer to the Study Reference 
Manual. 
11.4. 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each ICF must include all of the relevant elements currently required by the FDA, as 
well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patient, the patient’s consent to continue participation in the study should be obtained. 
11.4.1. 
Confidentiality 
11.4.1.1. Patient Confidentiality 
Confidentiality of patients’ personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of the following: 
• What protected health information (PHI) will be collected from patients in this study.   
• Who will have access to that information and why.   
• Who will use or disclose that information.   
• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed, the information may no longer be protected by federal 
or state privacy laws.   
• That the information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study.   
• Whether the authorization contains an expiration date.   


 
 
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• The rights of a research patient to revoke his or her authorization.   
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the Investigator and institution permit authorized representatives of the Sponsor, Development 
Innovations, the regulatory authorities, and the IRB direct access to review the patient’s original 
medical records at the site for verification of study-related procedures and data. 
One measure to protect confidentiality is that only a unique study number will identify patients 
in the eCRF database system or other documents submitted to the Sponsor or delegate and 
Development Innovations.  This information, together with the patient’s year of birth, will be 
used in the database for patient identification.  Patient names or addresses will not be entered in 
the eCRF database system.  No material bearing a patient’s name will be kept on file by the 
Sponsor or Development Innovations.  Patients will be informed of their rights within the ICF. 
11.4.1.2. Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the Sponsor and/or 
Development Innovations databases and shall be treated in compliance with all applicable laws 
and regulations.  When archiving or processing personal data pertaining to the Investigator or 
sub-Investigator, the Sponsor and/or Development Innovations shall take all appropriate 
measures to safeguard and prevent access to this data by any unauthorized party. 
11.5. 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between the 
Sponsor and applicable parties.  Any Investigator financial disclosures as applicable to 21CFR 
Part 54 shall be appropriately provided. 


 
 
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12. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
12.1. 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature-authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representative.  All amendments require review and approval of all 
pharmaceutical companies and the Principal Investigator supporting the study.  The written 
amendment must be reviewed and approved by the Sponsor and submitted to the IRB at the 
Investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase in dosing or 
exposure, patient number increase, or addition or removal of new tests or procedures shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable, and IRB/IEC approval obtained, specifically when an increase to dosing 
or patient exposure and/or patient number has been proposed; or, when the addition or removal 
of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB, IEC, and/or the FDA or other regulatory 
authorities’ approval include, but are not limited to, the following: 
• Change to study design.   
• Risk to patients.   
• Increase in dose or patient exposure to drug.   
• Patient number increase.   
• Addition or removal of tests and/or procedures.   
• Addition/removal of an Investigator.   
It should be further noted that if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 
12.2. 
Documentation Required to Initiate the Study 
Before the study can begin, certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
 
 
 
 
Documents required at a minimum to begin a study include, but are not limited to, the following: 
• A signature-authorized protocol and contract.   


 
 
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• A copy of the official IRB/IEC approval of the study and the IRB/IEC members list.   
• Current curricula vitae for the Principal Investigator and any associate Investigator(s) 
who will be involved in the study.   
• Indication of appropriate accreditation for laboratories (as required) to be used in the 
study and the normal ranges for tests to be performed by those laboratories.   
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed.   
• A copy of the IRB/IEC-approved ICF containing permission for audit by representatives 
of the Sponsor, Development Innovations, the IRB/IEC, and the FDA and other 
regulatory agencies (as applicable).   
• Financial disclosure forms for all Investigators listed on Form FDA 1572 (if applicable, 
i.e., for covered trials).   
• Verification of Principal Investigator acceptability from local and/or national debarment 
list(s).   
12.3. 
Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the eCRFs are to be included on this document.  All entries in the patients’ eCRFs are to be 
supported by source documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patients’ eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, x-rays, NGS testing results, and 
correspondence. 
The Principal Investigator and study staff members are responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or Investigator study file 
[ISF]) of all essential study-related documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain at a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, the protocol and any amendments, 
signed ICFs, copies of completed eCRFs, IRB/IEC approval documents, Financial Disclosure 
forms, patient identification lists, enrollment logs, delegation of authority log, staff qualification 
documents, laboratory normal ranges, and records relating to the study drug including 
accountability records.  Drug accountability records should, at a minimum, contain information 
regarding receipt, shipment, and disposition.  Each form of drug accountability record, at a 
minimum, should contain Principal Investigator name, date drug shipped/received, and the date, 


 
 
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quantity, and batch/code or lot number for the identity of each shipment.  In addition, all original 
source documents supporting entries in the eCRF must be maintained and readily available. 
The Sponsor shall maintain adequate investigational product and financial interest records as per 
21 CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application has 
been approved by the FDA or, in the event that the marketing application has not been approved 
by the FDA, for no less than 2 years after the last shipment/delivery of the drug for 
investigational use or the drug is discontinued, and the FDA has been notified of the 
discontinuation. 
The IRB shall maintain adequate documentation/records of IRB activities as per 21 CFR Part 
56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by the FDA or, in the event that the marketing 
application has not been approved by the FDA, for no less than 2 years after the last 
shipment/delivery of the drug for investigational use or the drug is discontinued, and the FDA 
has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records, e.g., eCRF and medical records), all 
original signed ICFs, copies of all eCRF records, SAE reporting forms, source documents, 
detailed records of treatment disposition, and related essential regulatory documents.  The 
documents listed above must be retained by the Investigator for as long as needed to comply with 
national and international regulations (generally 2 years after discontinuing clinical development 
or after the last marketing approval).  The Sponsor or its representative will notify the 
Investigator(s)/institutions(s) when the study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor or 
its representative must be prospectively notified.  The study records must be transferred to an 
acceptable designee, such as another Investigator, another institution, or to Development 
Innovations.  The Investigator must obtain the Sponsor’s written permission before disposing of 
any records, even if retention requirements have been met.  All study files will be maintained by 
the Sponsor or its representative throughout the study and will be transferred to the Sponsor at 
the conclusion of the study, if applicable. 
12.4. 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language, except for patient questionnaires for non-English 
speaking patients, and should be kept current to enable the Sponsor to review the patients’ status 
throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, and year of birth will 
identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to 
Development Innovations and be replaced instead with the patient number and other identifier 
(i.e., patient initials), as allowed per institutional policy.  The Investigator will maintain a 


 
 
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personal patient identification list (patient numbers with corresponding patient identifiers) to 
enable records to be identified and verified as authentic.  Patient data/information will be kept 
confidential and will be managed according to applicable local, state, and federal regulations. 
All data requested by the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done, or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the test was “Not Done,” or the result was “Unknown.”  
For any entry errors made, the error(s) must be corrected, and a note explaining the reason for 
change should be provided. 
The Investigator will electronically sign and date the patient eCRF indicating that the data in the 
eCRF has been assessed.  Each completed eCRF will be signed and dated by the Principal 
Investigator once all data for that patient is final. 
12.5. 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication process. 
For EU Only:  The Sponsor will disclose the study results in the form of a clinical study report 
synopsis to the IEC and the applicable regulatory authorities within one year of the end of the 
study (as defined in Section 4.4).  The format of this synopsis and that of the clinical study report 
should comply with ICH E3 guidelines for structure and content of a clinical study report. 
Inclusion of the Investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the study design, the analysis or interpretation of data, or the drafting 
and/or critically revising of any manuscript(s) derived from the study.  The Investigator 
acknowledges that the study is part of a multi-center study and agrees that any publication by the 
Investigator of the results of the study conducted at the research site shall not be made before the 
first multi-center publication.  In the event there is no multi-center publication within 15 months 
after the study has been completed or terminated at all study sites and all data has been received, 
the Investigator shall have the right to publish his/her results from the study, subject to the notice 
requirements described herein and subject to acknowledgement of the Sponsor as appropriate.  
The Investigator shall provide the Sponsor 30 days to review a manuscript or any poster 
presentation, abstract or other written or oral material which describes the results of the study for 
the purpose only of determining if any confidential or patentable information is disclosed 
thereby.  If the Sponsor requests in writing, the Investigator shall withhold any publication or 
presentation an additional 60 days solely to permit the Sponsor to seek patent protection and to 
remove any Development Innovations confidential information from all publications. 


 
 
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Bose et al. 2013 
Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene 
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Connell and Doherty 2017 
Connell CM, Doherty GJ. Activating HER2 mutations as emerging targets in multiple solid 
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Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and 
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Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies and new targeted 
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Hyman DM, Piha-Paul SA, Rodon J, Saura C, Shapiro GI, Quinn DI, et al. Abstract CT001: 
Neratinib in HER2 or HER3 mutant solid tumors: SUMMIT, a global, multi-histology, open-
label, phase 2 "basket" study. Cancer Res. 2017;77(13 suppl);CT001 
Hyman et al. 2018 
Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition patients with HER2- and HER3-
mutant cancers. Nature. 2018;554(7691):189-94. 
Kim et al. 2019 
Kim T, Ock CY, Kim M, Kim S, Keam B, Kim Y, et al. Phase II study of osimertinib in NSCLC 
patients with EGFR exon 20 insertion mutation: a multicenter trial of the Korean Cancer Study 
Group (LU17-19). Ann of Oncol. 2019:30(5 suppl):v628. 
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Le X, Goldman JW, Clarke JM, Tchekmedyian N, Piotrowska Z, Chu D, et al. Poziotinib shows 
activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC 
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Lindeman et al. 2018 
Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection 
of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the 
College of American Pathologists, the International Association for the Study of Lung Cancer, 
and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-58. 
Liu and Yuan 2015 
Liu S, Yuan Y. Bayesian optimal interval designs for Phase I clinical trials. J Soc: Series C. 
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Neumann et al. 2018 
Neumann MHD, Bender S, Krahn T, et al. ctDNA and CTCs in liquid biopsy current status and 
where we need progress. Comput Struct Biotechnol J. 2018;16:190-95. 
Oaknin et al. 2020 
Oaknin A, Friedman CF, Roman LD, D'Souza A, Brana I, Bidard FC, et al. Neratinib in patients 
with HER2-mutant, metastatic cervical cancer: findings from the phase 2 SUMMIT basket trial. 
Gynecol Oncol. 2020;159(1):150-6. 
Oxnard et al. 2013 
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molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 
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Pahuja et al. 2018 
Pahuja KB, Nguyen TT, Jaiswal BS, et al. Actionable activating oncogenic ERBB2/HER2 
transmembrane and juxtamembrane domain mutations. Cancer Cell. 2018;34(5):792-806. 
Park et al. 2020 
Park K, John T, Kim S, Lee JS, Shu CA, Kim DW, et al. Amivantamab (JNJ-61186372), an anti-
EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated 
non-small cell lung cancer (NSCLC). J Clin Oncol.  2020;38(15 suppl):9512. 


 
 
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Piotrowska Z, Wang Y, Sequist LV, Ramalingam SS.  ECOG-ACRIN 5162: A phase II study of 
osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol.  2020;38(15 
suppl):9513. 
Riely et al. 2020 
Riely G, Neal J, Camidge D, Spira A, Piotrowska Z, Horn L, et al. 1261MO Updated results 
from a phase I/II study of mobocertinib (TAK-788) in NSCLC with EGFR exon 20 insertions 
(exon20ins). Ann of Oncol. 2020;31:S815-S816. 
Robichaux et al. 2018 
Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 
exon 20 selective kinase inhibitor in non small cell lung cancer. Nat Med. 2018;24(5):638-46. 
Simon 1989 
Simon, R. Optimal two-stage designs for Phase II clinical trials. Controlled Clin Trials. 
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Smit et al. 2020 
Smit EF, Nakagawa K, Nagasaka M, Felip E, Goto Y, Li BT, et al. Trastuzumab deruxtecan (T-
DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): 
Interim results of DESTINY-Lung01.  J Clin Oncol.  2020;38(15 suppl):9504. 
Socinski et al. 2020 
Socinski M, Cornelissen R, Garassino M, Clarke J, Tchekmedyian N, Molina J, et al. LBA60 
ZENITH20, a multinational, multi-cohort phase II study of poziotinib in NSCLC patients with 
EGFR or HER2 exon 20 insertion mutations. Ann of Oncol.  2020;31(4 suppl):S1188. 
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Stern HM. Improving treatment of HER2-positive cancers: opportunities and challenges. Sci 
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Takeda M, Sakai K, Hayashi H, et al. Clinical characteristics of non small cell lung cancer 
harboring mutations in exon 20 of EGFR or HER2. Oncotarget. 2018;9(30):21132-40. 
Tomaras et al. 2020 
Tomaras D, Lin H, Forsythe A, Crossland V, Ou SI. 1362P Clinical and real-world outcomes in 
patients with epidermal growth factor receptor (EGFR) exon 20 insertions in non-small cell lung 
cancer (NSCLC): meta-analysis. Ann of Oncol. 2020;31:S871. 
Wen et al. 2015 
Wen W, Chen WS, Xiao N, et al. Mutations in the kinase domain of the HER2/ERBB2 gene 
identified in a wide variety of human cancers. J Mol Diagn. 2015;17(5):487-95. 
Yuan et al. 2016 
Yuan Y, Hess KR, Hilsenbeck SG, et al. Bayesian optimal interval design: A simple and well-
performing design for phase I oncology trials. Clin Cancer Res. 2016;22(17):4291-301


 
 
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Appendix A Eastern Cooperative Oncology Group Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction. 
 
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours. 
 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
 
40 
Disabled, requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated.  Death 
not imminent. 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 
 


 
 
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Appendix B Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Definitions 
Response and progression will be evaluated in this trial using the RECIST v1.1 (Eisenhauer et al. 
2009).  Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used, as it does not provide additional 
meaning or accuracy. 
Baseline Eligibility 
Measurable Disease: 
Tumor lesions:  Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of: 
• 10 mm by CT by computed tomography (CT scan slice 
thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions that 
cannot be accurately measured with calipers should be 
recorded as non-measurable). 
• 20 mm by chest x-ray. 
 
Skin lesions:  Documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
Malignant lymph nodes:  To be considered pathologically 
enlarged and measurable, a lymph node must be ≥15 mm in short 
axis when assessed by CT scan.  At baseline and in follow-up, 
only the short axis will be measured and followed.  
Non-Measurable Disease: 
All other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with ≥10- to <15-mm short 
axis) as well as truly non-measurable lesions.  Lesions considered 
truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses, and 
abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.  


 
 
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Target Lesions: 
The most reproducible measurable lesions, up to a maximum of 
2 lesions per organ and 5 lesions in total, representative of all 
involved organs should be identified as target lesions and 
recorded and measured at baseline.   
Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), should be representative of 
all involved organs, and in addition should be those that lend 
themselves to reproducible repeated measurements.  Pathological 
nodes which are defined as measurable and that may be identified 
as target lesions must meet the criterion or a short axis of ≥15 
mm by CT scan. 
A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is 
added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor response. 
Non-Target Lesions: 
All other lesions should be identified as non-target lesions at 
baseline.  Measurements of these lesions are not required, but 
the presence or absence of each should be noted throughout 
follow-up. 
 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment, as 
per protocol screening requirements. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
Clinical Lesions: 
Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and 
≥10 mm in diameter.  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
Chest X-ray: 
Lesions on chest X-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, a CT scan is preferable. 


 
 
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Conventional CT and MRI: 
CT, MRI:  CT is the best currently available and reproducible 
method to measure lesions selected for response assessment.  
This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5mm or less.  
When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g., for 
body scans).  
Ultrasound: 
When the primary trial endpoint is objective response, ultrasound 
should not be used to measure tumor lesions.  It is, however, a 
possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions, and thyroid 
nodules.  Ultrasound may also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical 
examination. 
Endoscopy and 
Laparoscopy: 
Use of endoscopy and laparoscopy for objective tumor 
evaluation has not yet been fully and widely validated.  
Therefore, use of these techniques for objective tumor response 
should be restricted to validation purposes in specialized centers.  
Such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
Tumor Markers: 
Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper limit of normal, they must 
normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
Cytology and Histology: 
Cytology and histology can be used to differentiate between 
partial response (PR) and complete response (CR) in rare cases 
(e.g., after treatment to differentiate between residual benign 
lesions and residual malignant lesions in tumor types such as 
germ cell tumors). 
 


 
 
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Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR):  
Disappearance of all target lesions.   
Partial Response (PR):  
 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Stable Disease (SD):   
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest (nadir) 
sum of diameters since the treatment started. 
Progressive Disease (PD):   
 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest (nadir) sum since the 
treatment started, or the appearance of one or more new lesions.  
Requires not only 20% increase, but absolute increase of a 
minimum of 5 mm over sum. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor markers.  All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
Non-CR/Non-PD:    
 
Persistence of one or more non-target lesions and/or persistence 
of tumor marker level above the normal limits. 
Progressive Disease (PD):  
 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  When the patient also 
has measurable disease, to achieve “unequivocal progression” on 
the basis of the non-target disease, there must be an overall level 
of substantial worsening in non-target disease such that, even in 
presence of SD or PR in the target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of 
therapy. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started).  In general, the patient’s best response assignment will depend on 
the achievement of both measurement and confirmation criteria.   
Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is 
required for trials in which response rate is the primary endpoint but is not required in 
randomized trials or trials with primary survival endpoints (i.e., where response is not a primary 
endpoint). 
Note that a best overall response of SD requires an assessment of SD or better at the time of the 
first protocol-specified post-baseline tumor assessment (i.e., 42 days +/- 3 days after first dose) 
or later. 


 
 
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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
NO 
CR 
CR 
NON-CR/NON-PD 
NO 
PR 
CR 
NE 
NO 
PR 
PR 
NON-CR/NON-PD OR NE 
NO 
PR 
SD 
NON-CR/NON-PD OR NE 
NO 
SD 
NOT ALL EVALUATED 
NON-PD 
NO 
NE 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When the evaluation 
of a CR depends upon this determination, it is recommended that the residual lesion be investigated by fine needle 
aspirate or biopsy to confirm the CR status.  
When nodal disease is included in the sum of target lesions, and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression, should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero” on the eCRF. 


 
 
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Appendix C Guidelines for Women of Childbearing Potential and Fertile Male Patients 
Acceptable Contraception Methods: 
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for at least 90 days after 
stopping treatment. 
Highly effective contraception is defined as either: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Sterilization 
When a woman of childbearing potential has had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks prior to study entry.  In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up 
hormone level assessment. 
Male Partner 
Sterilization 
When there is appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate. 
Use of the following: 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) or 
established use of oral, injected or implanted hormonal methods of 
contraception, bilateral tubal occlusion, vasectomized partner. 
Fertile male patients, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus a spermicidal agent during the 
study treatment period and for at least 90 days after the last dose of study drug, and should not 
father a child during this period. 
Male patients must also refrain from donating sperm during their participation in the study. 
Unacceptable Contraception Methods for women of childbearing potential include: 
• IUD progesterone T.   
• Female condom.   
• Natural family planning (rhythm method) or breast-feeding.   
• Fertility awareness.   
• Withdrawal.   
• Cervical shield.   
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to the 
Development Innovations Safety Department within 24 hours of learning of its occurrence.  The 


 
 
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pregnancy should be followed up for 3 months after the termination of the pregnancy to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or new-born complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
Investigator to the Development Innovations Safety Department.  Pregnancy follow-up should 
be recorded on the same form and should include an assessment of the possible relationship to the 
study drug of any pregnancy outcome.  Any SAE experienced during pregnancy must be reported 
on the SAE paper report form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
Women Not of Childbearing Potential are defined as follows: 
• Women are considered post-menopausal and not of childbearing potential if they have had 
continuous 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g., age appropriate, history of vasomotor symptoms). 
• Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy). 
• Women who are >45 years-of-age, not using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 12 months OR who have a follicle 
stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL 
(140 pmol/L). 
• Women who are >45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to 
initiation of hormone-replacement therapy. 


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




 
 
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Appendix F Drugs That Induce Torsades De Pointes 
Drugs with a known risk of Torsades de pointes should be avoided for all patients from screening 
through permanent discontinuation of study treatment.   
Some of the medications listed may be allowed at the Investigator’s discretion after approval by 
the Medical Monitor when the patient has unmet medical need to continue receiving prohibited 
medication(s), no suitable alternative treatments are available, and the benefit-risk ratio is 
acceptable in the Investigator’s opinion. 
CredibleMeds® (www.crediblemeds.org) is the standard reference for drugs with known or 
possible risk of Torsades de Pointes.  Since CredibleMeds® constantly assesses new drug 
information and updates its lists, sites should go directly to the crediblemeds.org website in real-
time for reference.  Patients receiving drugs listed in the “known” or “possible” categories at the 
time of eligibility assessment are prohibited from 14 days before the start of treatment until 
permanent discontinuation of treatment. 
 
 


 
 
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Appendix G Operating Characteristics of the Bayesian Optimal Interval Design 
Operating Characteristics of the BOIN Design for QD Dosing Schedule 
  
Dose Level (mg) 
Mean # of 
Patients 
% Early 
Stopping 
  
1 
(25) 
2 
(50) 
3 
(100) 
4 
(200) 
5 
(400) 
6 
(800) 
7 
(1200) 
8 
(1600) 
Scenario 1 
True DLT Rate 
0.11 
0.30 
0.46 
0.48 
0.51 
0.53 
0.56 
0.58 
24.70 
0.1 
Selection % 
19.3 
53.5 
16.7 
6.5 
2.6 
0.9 
0.2 
0.2 
# Pts Treated 
4.9 
9.5 
5.6 
2.6 
1.3 
0.5 
0.2 
0.1 
Scenario 2 
True DLT Rate 
0.04 
0.08 
0.12 
0.16 
0.30 
0.47 
0.54 
0.60 
27.92 
0.0 
Selection % 
0.1 
1.4 
4.8 
22.3 
50.0 
16.8 
3.6 
1.0 
# Pts Treated 
1.3 
1.8 
2.7 
5.7 
8.8 
5.0 
1.9 
0.7 
Scenario 3 
True DLT Rate 
0.04 
0.07 
0.10 
0.12 
0.15 
0.30 
0.48 
0.68 
28.59 
0.0 
Selection % 
0.4 
0.8 
2.3 
4.5 
19.9 
54.8 
16.0 
1.3 
# Pts Treated 
1.2 
1.6 
2.2 
2.7 
5.2 
9.2 
5.2 
1.3 
Scenario 4 
True DLT Rate 
0.02 
0.04 
0.06 
0.08 
0.10 
0.12 
0.30 
0.45 
28.33 
0.0 
Selection % 
0.0 
0.1 
0.8 
1.9 
3.2 
20.5 
51.7 
21.8 
# Pts Treated 
1.1 
1.3 
1.6 
2.0 
2.3 
5.3 
8.9 
5.9 
Abbreviations:  DLT = dose-limiting toxicity; Pts = patients. 
 


 
 
Study Drug:  BDTX-189 Sponsor/ Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
Protocol Amendment 3 (Version 4.0): 08 June 2021   
Confidential 
Page 130 of 151 
Operating Characteristics of the BOIN Design for BID Dose Schedule 
  
Dose Level 
Number of 
Patients 
% Early 
Stopping 
  
1 
2 
3 
4 
Scenario 1 
True DLT Rate 
0.30 
0.47 
0.55 
0.64 
18.12 
13.5 
Selection % 
68.1 
16.1 
2.3 
0.0 
# Pts Treated 
12.1 
5.1 
0.8 
0.1 
Scenario 2 
True DLT Rate 
0.11 
0.30 
0.45 
0.67 
22.55 
0.4 
Selection % 
21.8 
55.0 
21.2 
1.6 
# Pts Treated 
7.4 
9.7 
4.7 
0.8 
Scenario 3 
True DLT Rate 
0.02 
0.13 
0.30 
0.47 
23.56 
0.0 
Selection % 
0.6 
24.0 
55.5 
19.9 
# Pts Treated 
3.5 
7.1 
8.8 
4.2 
Scenario 4 
True DLT Rate 
0.05 
0.10 
0.15 
0.30 
23.75 
0.0 
Selection % 
0.9 
5.4 
26.3 
67.4 
# Pts Treated 
3.7 
4.7 
6.3 
9.0 
Abbreviations:  DLT = dose-limiting toxicity; Pts = patients. 
 
 


 
 
Study Drug:  BDTX-189 Sponsor/ Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
Protocol Amendment 3 (Version 4.0): 08 June 2021   
Confidential 
Page 131 of 151 
Appendix H Flowchart for Trial Conduct 
Flowchart for Trial Conduct Using the BOIN Design 
 
Abbreviations:  BOIN = Bayesian optimal interval; DLT = dose-limiting toxicity; MTD = maximum tolerated dose 




 
 
Study Drug:  BDTX-189 Sponsor/ Development Innovations Study Numbers: BDTX-189-01/REFMAL 648 
Protocol Amendment 3 (Version 4.0): 08 June 2021   
Confidential 
Page 133 of 151 
Appendix J 
Adverse Events Severity Grading Guideline 
Adverse events will be reported at the highest experienced.  Adverse events severity will be 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE v 5.0.)  A copy of the document will be provided to investigational sites 
and an electronic version is available at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf 
Events not listed in NCI CTCAE will be graded according to the criteria described in the table 
below: 
Severity Grading Guideline for Adverse Events not listed in NCI CTCAE V5.0 
Adverse Events not Listed in NCI CTCAE V5.0 
Grade 
Description 
1 
Mild; 
Asymptomatic or mild symptoms; 
Clinical or diagnostic observations only; 
Intervention not indicated 
2 
Moderate; 
Minimal, local or noninvasive intervention indicated; 
Limiting age-appropriate instrumental ADL* 
3 
Severe or medically significant but not immediately life threatening; 
Hospitalization or prolongation of hospitalization indicated; 
Disabling; 
Limiting self-care ADL** 
4 
Life-threatening consequences; 
Urgent intervention indicated 
5 
Death related to AE 
Abbreviations:  ADL = activity of daily living; AE = adverse event 
Adapted from NCI-CTCAE V5.0 
Note: A Semicolon indicates ‘or’ within the description of the grade. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.   
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.