NSCLC
Conditions
Brief summary
This clinical trial is the first-in-human study of BBT-176. The purpose of this trial is to investigate the safety and tolerability of BBT-176 (Part 1) and to evaluate the anti-tumor activity of BBT-176 (Part 2).
Interventions
DRUGBBT-176, QD
BBT-176 given orally alone, QD
DRUGBBT-176, BID
BBT-176 given orally alone, BID
Sponsors
Bridge Biotherapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Provision of signed and dated, written informed consent before any study specific procedures, sampling and analyses * Histological or cytological confirmation of advanced and/or metastatic stage IIIB/IV NSCLC * Radiological documentation of disease progression while on a previous continuous (at least 30 days) treatment with an EGFR TKI monotherapy (including, but not limited to, osimertinib, afatinib, gefitinib, or erlotinib) * Patients must fulfill one of the following: * Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including, but not limited to, exon 19 deletion, L858R, or L861Q) * Documented partial or complete response or a significant and durable stable disease (at least 6 months), based on the RECIST or WHO criteria, after treatment of an EGFR TKI Key
Exclusion criteria
* Treatment with any of the following: * An EGFR TKI, including but not limited to osimertinib, afatinib, gefitinib, or erlotinib within 8 days of the first dose of study treatment. * Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for the treatment of advanced NSCLC, between prior EGFR TKI treatment and BBT-176 treatment * Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment * Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment * Patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation within 6 weeks of the first dose of study treatment * Any unresolved toxicities from prior therapy greater than NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) Grade 1 at the time of starting study treatment, with the exception of alopecia and Grade 2 neuropathy related to prior platinum-therapy * Spinal cord compression or brain metastases, unless asymptomatic and stable
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 21 days from the first dosing | Any toxicity not attributable to the disease or disease-related processes under investigation that occurs from the first dose of study treatment in dose-escalation cohorts as defined in the protocol. |
| (Part 2) Objective Response Rate (ORR) | Every 6 weeks | ORR is estimated by the number of patients with a best overall response of CR or PR divided by the total number of patients who are evaluable for efficacy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 0, 1, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 (C1D1) and Cycle 2 Day 1 (C2D1) (each cycle is 21 days) | Area under the plasma concentration-time curve (AUC) of BBT-176 from Part 1. |
| (Part 2) Duration of Response (DoR) | throughout study completion, approximately 1 year | DoR is calculated for every patient with a response to therapy (PR and CR) and is defined as the number of days from the date of initial response to the date of the first documented disease progression/relapse (including clinical progression) or death, whichever occurs first. |
| (Part 1) Objective Response Rate (ORR) | Every 6 weeks, approximately 1 year | ORR is estimated by the number of patients with a best overall response of Complete Response (CR) or Partial Response (PR) divided by the total number of patients who are evaluable for efficacy. |
| (Part 2) BBT-176 Concentrations | At Cycle 2 Day 1 (each cycle is 21 days) | Plasma BBT-176 concentrations at steady state |
| (Part 2) Progression Free Survival (PFS) | throughout study completion, approximately 1 year | PFS will be calculated for each patient as the number of days from the first day of treatment to the date of the first documented disease progression or date of death, whichever occurs first. |
| (Part 2) Incidence of Adverse Event (AE)s | throughout study completion, approximately 1 year | Number of patients experiencing adverse event (AE)s |
| (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 0, 1, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 (C1D1) and Cycle 2 Day 1 (C2D1) (each cycle is 21 days) | Peak plasma concentration (Cmax) of BBT-176 from Part 1. |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 20mg QD BBT-176: 20mg, Orally, QD | 4 |
| 80mg QD BBT-176: 80mg, Orally, QD | 3 |
| 160mg QD BBT-176: 160mg, Orally, QD | 4 |
| 320mg QD BBT-176: 320mg, Orally, QD | 3 |
| 480mg QD BBT-176: 480mg, Orally, QD | 8 |
| 600mg QD BBT-176: 600mg, Orally, QD | 3 |
| 160mg BID BBT-176: 160mg, Orally, BID | 5 |
| 200mg BID BBT-176: 200mg, Orally, BID | 9 |
| 240mg BID BBT-176: 240mg, Orally, BID | 6 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | New anti-cancer therapy | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Progressive Disease | 3 | 0 | 2 | 2 | 2 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 2 | 1 | 4 | 3 | 3 | 6 | 5 |
Baseline characteristics
| Characteristic | 20mg QD | Total | 240mg BID | 200mg BID | 160mg BID | 600mg QD | 480mg QD | 320mg QD | 160mg QD | 80mg QD |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 6.5 | 62.1 years STANDARD_DEVIATION 10.5 | 65.5 years STANDARD_DEVIATION 7.1 | 62.3 years STANDARD_DEVIATION 10.5 | 63.2 years STANDARD_DEVIATION 9.4 | 73.0 years STANDARD_DEVIATION 5.3 | 63.9 years STANDARD_DEVIATION 10.1 | 50.0 years STANDARD_DEVIATION 10.1 | 48.0 years STANDARD_DEVIATION 9.1 | 62.3 years STANDARD_DEVIATION 11.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 45 Participants | 6 Participants | 9 Participants | 5 Participants | 3 Participants | 8 Participants | 3 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 31 Participants | 5 Participants | 7 Participants | 2 Participants | 2 Participants | 6 Participants | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 14 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 4 | 0 / 3 | 0 / 8 | 0 / 3 | 1 / 5 | 0 / 9 | 1 / 6 |
| other Total, other adverse events | 3 / 4 | 2 / 3 | 3 / 4 | 3 / 3 | 8 / 8 | 3 / 3 | 4 / 5 | 9 / 9 | 6 / 6 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 2 / 4 | 1 / 3 | 4 / 8 | 1 / 3 | 3 / 5 | 6 / 9 | 6 / 6 |
Outcome results
Primary
(Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs)
Any toxicity not attributable to the disease or disease-related processes under investigation that occurs from the first dose of study treatment in dose-escalation cohorts as defined in the protocol.
Time frame: 21 days from the first dosing
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 20mg QD | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 0 Participants |
| 80mg QD | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 0 Participants |
| 160mg, QD | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 0 Participants |
| 320mg, QD | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 0 Participants |
| 480mg, QD | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 0 Participants |
| 600mg, QD | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 0 Participants |
| 160mg, BID | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 0 Participants |
| 200mg, BID | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 1 Participants |
| 240mg, BID | (Part 1) Incidence of Adverse Events and Clinical Laboratory Abnormalities Defined as Dose-limiting Toxicities (DLTs) | 1 Participants |
Primary
(Part 2) Objective Response Rate (ORR)
ORR is estimated by the number of patients with a best overall response of CR or PR divided by the total number of patients who are evaluable for efficacy.
Time frame: Every 6 weeks
Population: Due to early termination of the study, Part 2 and analysis was not conducted.
Secondary
(Part 1) Objective Response Rate (ORR)
ORR is estimated by the number of patients with a best overall response of Complete Response (CR) or Partial Response (PR) divided by the total number of patients who are evaluable for efficacy.
Time frame: Every 6 weeks, approximately 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 20mg QD | (Part 1) Objective Response Rate (ORR) | 0 Participants |
| 80mg QD | (Part 1) Objective Response Rate (ORR) | 0 Participants |
| 160mg, QD | (Part 1) Objective Response Rate (ORR) | 1 Participants |
| 320mg, QD | (Part 1) Objective Response Rate (ORR) | 0 Participants |
| 480mg, QD | (Part 1) Objective Response Rate (ORR) | 0 Participants |
| 600mg, QD | (Part 1) Objective Response Rate (ORR) | 0 Participants |
| 160mg, BID | (Part 1) Objective Response Rate (ORR) | 0 Participants |
| 200mg, BID | (Part 1) Objective Response Rate (ORR) | 0 Participants |
| 240mg, BID | (Part 1) Objective Response Rate (ORR) | 1 Participants |
Secondary
(Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax)
Peak plasma concentration (Cmax) of BBT-176 from Part 1.
Time frame: 0, 1, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 (C1D1) and Cycle 2 Day 1 (C2D1) (each cycle is 21 days)
Population: The presentation of PK data on C1D1 and C2D1 was due to that the PK samples were collected on those dates.~PK samples were collected at 600 mg QD, but drug exposure was low due to vomiting, making it impossible to determine PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 20mg QD | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 7 ng/mL | Standard Deviation 4 |
| 80mg QD | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 10 ng/mL | Standard Deviation 5 |
| 160mg, QD | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 159 ng/mL | Standard Deviation 67 |
| 320mg, QD | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 260 ng/mL | Standard Deviation 37 |
| 480mg, QD | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 240 ng/mL | Standard Deviation 75 |
| 600mg, QD | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 638 ng/mL | Standard Deviation 231 |
| 160mg, BID | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 594 ng/mL | Standard Deviation 94 |
| 200mg, BID | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 1416 ng/mL | Standard Deviation 370 |
| 240mg, BID | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 1087 ng/mL | Standard Deviation 470 |
| 480mg QD C2D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 2145 ng/mL | Standard Deviation 1438 |
| 600mg QD C1D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | NA ng/mL | — |
| 600mg QD C2D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | NA ng/mL | — |
| 160mg BID C1D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 255 ng/mL | Standard Deviation 80 |
| 160mg BID C2D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 1186 ng/mL | Standard Deviation 695 |
| 200mg BID C1D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 354 ng/mL | Standard Deviation 88 |
| 200mg BID C2D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 1784 ng/mL | Standard Deviation 358 |
| 240mg BID C1D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 399 ng/mL | Standard Deviation 154 |
| 240mg BID C2D1 | (Part 1) Pharmacokinetics (PK) Parameters - Peak Concentration (Cmax) | 1622 ng/mL | Standard Deviation 472 |
Secondary
(Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC)
Area under the plasma concentration-time curve (AUC) of BBT-176 from Part 1.
Time frame: 0, 1, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 (C1D1) and Cycle 2 Day 1 (C2D1) (each cycle is 21 days)
Population: PK data were presented on C1D1 and C2D1 as samples were collected on those days. In the BID regimen, AUC 0-12 was calculated on both days. AUC 0-24 was estimated on C2D1 using AUC 0-12, assuming steady state, but not on C1D1 since steady state was not reached. In Cohort 6 (600mg QD), PK parameters were not determined as BBT-176 was not tolerable, and drug exposure was low due to vomiting.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 20mg QD | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 91 ng*hr/mL | Standard Deviation 42 |
| 80mg QD | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 192 ng*hr/mL | Standard Deviation 89 |
| 160mg, QD | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 1314 ng*hr/mL | Standard Deviation 263 |
| 320mg, QD | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 3584 ng*hr/mL | Standard Deviation 158 |
| 480mg, QD | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 2799 ng*hr/mL | Standard Deviation 1030 |
| 600mg, QD | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 9652 ng*hr/mL | Standard Deviation 5978 |
| 160mg, BID | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 8065 ng*hr/mL | Standard Deviation 2703 |
| 200mg, BID | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 21992 ng*hr/mL | Standard Deviation 5494 |
| 240mg, BID | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 13938 ng*hr/mL | Standard Deviation 6315 |
| 480mg QD C2D1 | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 38365 ng*hr/mL | Standard Deviation 21815 |
| 600mg QD C1D1 | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | NA ng*hr/mL | — |
| 600mg QD C2D1 | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | NA ng*hr/mL | — |
| 160mg BID C1D1 | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 20842 ng*hr/mL | Standard Deviation 11511 |
| 160mg BID C2D1 | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 37564 ng*hr/mL | Standard Deviation 8612 |
| 200mg BID C1D1 | (Part 1) PK Parameters - Area Under the Concentration-time Curve (AUC) | 33521 ng*hr/mL | Standard Deviation 9070 |
Secondary
(Part 2) BBT-176 Concentrations
Plasma BBT-176 concentrations at steady state
Time frame: At Cycle 2 Day 1 (each cycle is 21 days)
Population: Due to early termination of the study, Part 2 and analysis was not conducted.
Secondary
(Part 2) Duration of Response (DoR)
DoR is calculated for every patient with a response to therapy (PR and CR) and is defined as the number of days from the date of initial response to the date of the first documented disease progression/relapse (including clinical progression) or death, whichever occurs first.
Time frame: throughout study completion, approximately 1 year
Population: Due to early termination of the study, Part 2 and analysis was not conducted.
Secondary
(Part 2) Incidence of Adverse Event (AE)s
Number of patients experiencing adverse event (AE)s
Time frame: throughout study completion, approximately 1 year
Population: Due to early termination of the study, Part 2 and analysis was not conducted.
Secondary
(Part 2) Progression Free Survival (PFS)
PFS will be calculated for each patient as the number of days from the first day of treatment to the date of the first documented disease progression or date of death, whichever occurs first.
Time frame: throughout study completion, approximately 1 year
Population: Due to early termination of the study, Part 2 and analysis was not conducted.