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Report for Clinical Trial NCT04209465

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

MasterKey-01: A Phase 1/2, Open-label, Two-part, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics & Antitumor Activity of BDTX-189, an Inhibitor of Allosteric ErbB Mutations, in Patients w/ Advanced Solid Malignancies

This is a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that have 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 are 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 antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

NCT04209465 Solid Tumor

1 Interventions

Name: BDTX-189

Description: Participants will receive a daily, oral dose of BDTX-189 as part of a 3 week cycle.
Type: Drug
Group Labels: 2

Phase 1 - Dose escalation Phase 2 - Dose expansion


Primary Outcomes

Description: Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease.

Measure: Incidence of dose limiting toxicities as a determinant of the Recommended Phase 2 Dose (RP2D)

Time: After the first dose of treatment for up to 21 days.

Description: Objective response rate is defined as the proportion of participants who achieve a confirmed complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 2: Objective response rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Secondary Outcomes

Description: Adverse events will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Measure: Phase 1 and Phase 2: Incidence of treatment-emergent adverse events as a measure of safety and tolerability of BDTX-189

Time: From Cycle 1 Day 1 (each cycle is 21 days) until 30 days post last dose

Description: Blood samples will be taken to measure the plasma concentrations of BDTX-189 in both a fed and fasted state.

Measure: Phase 1 and Phase 2: Plasma concentration of BDTX-189 as a measure of pharmacokinetics

Time: Multiple time points during Cycles 1-4 (each cycle is 21 days)

Description: Objective response is defined as the proportion of participants who achieved a complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 1: Objective response rate as a preliminary measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Duration of response is the time from first documentation of a response to first evidence of progressive disease per RECIST version 1.1 or death. A response is defined as either a complete response (CR; disappearance of all target lesions and non-target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions). Progressive disease is defined by a target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions.

Measure: Phase 1 and Phase 2: Duration of response as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Disease control rate is defined as the proportion of participants achieving: a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; at least a 30% decrease in the sum of diameters of target lesions), or stable disease (SD; neither sufficient shrinkage to qualify for a PR nor sufficient increase in lesions) per RECIST version 1.1.

Measure: Phase 1 and Phase 2: Disease control rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Progression-free survival is the time from first study dose until disease progression (PD; target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions) per RECIST v1.1.

Measure: Phase 1 and Phase 2: Progression-free survival as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Overall survival is the time from first study dose until death from any cause or study discontinuation.

Measure: Phase 2: Overall survival as a measure of clinical activity

Time: Assessed every 12 weeks after treatment discontinuation for up to 1 year

Purpose: Treatment

Allocation: Non-Randomized

Sequential Assignment


There are 9 SNPs

SNPs


1 C797S

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Solid Tumor 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. --- T790M --- --- C797S ---


2 C805S

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Solid Tumor 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. --- T790M --- --- C797S --- --- C805S ---


3 L755S

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R --- --- S310F --- --- R678Q --- --- L755S ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R --- --- S310F --- --- R678Q --- --- L755S ---

Phase 2 will focus on patients with a solid tumor harboring an: - Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) - EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- S310F --- --- R678Q --- --- L755S ---


4 L858R

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R ---

Phase 1 will focus on patients with a solid tumor 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 Following selection of the RP2D, a Phase 2 portion will be initiated to further evaluate the clinical activity of BDTX-189. --- L858R ---


5 R678Q

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R --- --- S310F --- --- R678Q ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R --- --- S310F --- --- R678Q ---

Phase 2 will focus on patients with a solid tumor harboring an: - Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) - EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- S310F --- --- R678Q ---


6 S310F

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R --- --- S310F ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R --- --- S310F ---

Phase 2 will focus on patients with a solid tumor harboring an: - Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) - EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- S310F ---


7 T790M

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Solid Tumor 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. --- T790M ---


8 V777L

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R --- --- S310F --- --- R678Q --- --- L755S --- --- V777L ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R --- --- S310F --- --- R678Q --- --- L755S --- --- V777L ---

Phase 2 will focus on patients with a solid tumor harboring an: - Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) - EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- S310F --- --- R678Q --- --- L755S --- --- V777L ---


9 V842I

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R --- --- S310F --- --- R678Q --- --- L755S --- --- V777L --- --- V842I ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - 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 - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R --- --- S310F --- --- R678Q --- --- L755S --- --- V777L --- --- V842I ---

Phase 2 will focus on patients with a solid tumor harboring an: - Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) - EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- S310F --- --- R678Q --- --- L755S --- --- V777L --- --- V842I ---



HPO Nodes