This is a first-in-human, open label, Phase 1/2 study to investigate the safety and efficacy of TAS3351 in participants with advanced or metastatic non-small cell lung cancer (NSCLC) harboring an acquired C797S epidermal growth factor receptor (EGFR) mutation.
This study will be conducted in 3 parts (i.e. dose escalation, dose expansion, and a phase 2 portion). The dose escalation part will investigate the safety and determine the recommended phase 2 dose and the recommended dosing regimen of TAS3351 administered orally. The dose expansion part will explore the efficacy of TAS3351 in NSCLC participants with C797S EGFR mutations. The phase 2 part will assess the efficacy of TAS3351 in NSCLC participants with C797S EGFR mutations.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Oral tablets.
Tennessee Oncology
Nashville, Tennessee, United States
University of Texas M. D. Anderson Cancer Center
Houston, Texas, United States
Next Oncology - Virginia
Fairfax, Virginia, United States
Institut Gustave Roussy
Villejuif, Val De Marne, France
Part A1: Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; it did not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an AE that started or worsened at the time of or after the first dose of study drug administration and within 30 days after the last dose of study drug and did not necessarily have a causal relationship to the use of the study drug.
Time frame: From first dose of the study drug up to 30 days after last dose (up to 21.7 months)
Part A1: Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs were defined as adverse events (AEs) graded by Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) assessed by the Investigator to be related to study treatment administration during Cycle 1 \& included:Hematologic Toxicity;grade 4 neutropenia greater than\[\>\]7days; febrile neutropenia (absolute neutrophil count \[ANC\] less than(\<)1000 per cubic millimeter (1000/mm3) with fever greater than or equal to(≥)38.3 degree celsius (°C) or fever ≥38.0°C for \> 1hour); grade 4 thrombocytopenia, Hepatic Toxicity: grade ≥3 total bilirubin \>7days; grade 4 total bilirubin; Renal Toxicity:creatinine clearance(CrCl)\<30 milliliters per minute (mL/min) for \> 3days despite supportive care;Other Nonhematologic Toxicity:grade ≥3 nonhematologic toxicity with: grade 3 nausea, vomiting, diarrhea, or hyperglycemia, prolonged delay (\>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Any death not clearly attributed to the underlying disease or extraneous causes.
Time frame: Cycle 1 (cycle length = 21 days)
Part B: Dose Expansion: Percentage of Participants With Objective Response Rate (ORR) by Independent Central Review (ICR)
ORR was the proportion of participants experiencing a best overall response of partial response (PR) or complete response (CR) according to response evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) criteria. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30 percent (%) decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to less than (\<)10 millimeters (mm).
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Universitaetsklinikum Koeln
Cologne, North Rhine-Westphalia, Germany
National Cancer Center Hospital East
Kashiwa-shi, Chiba, Japan
Shizuoka Cancer Center
Sunto-gun, Shizuoka, Japan
Leiden University Medical Center (LUMC)
Leiden, Netherlands
Time frame: Up to 21.7 months
Part C: Phase 2: Percentage of Participants With ORR by ICR
ORR was the proportion of participants experiencing a PR or CR according to RECIST v1.1 criteria. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10mm.
Time frame: Up to approximately 21.7 months
Part A1: Dose Escalation: Percentage of Participants With ORR
ORR was the proportion of participants experiencing a best overall response of PR or CR according to RECIST v1.1 criteria. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10mm.
Time frame: From first dose of the study drug up to 30 days after the last dose (up to approximately 21.7 months)
Part A1: Dose Escalation: Duration of Response (DoR)
DOR was calculated for all responders from the date of first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10 mm.
Time frame: From first dose of the study drug up to 30 days after the last dose (up to approximately 21.7 months)
Part A1: Dose Escalation: Percentage of Participants Exhibiting Disease Control Rate (DCR)
DCR was the proportion of participants who achieved a CR, PR, or stable disease (SD). Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis \<10 mm. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), referencing the smallest sum diameters while on study.
Time frame: From first dose of the study drug up to 30 days after the last dose (up to approximately 21.7 months)
Part A2: Backfill: Number of Participants Exhibiting Progression Free Survival (PFS)
PFS was defined as the time from date of first dose to the date of documentation of disease progression, or date of death, whichever occurred first.
Time frame: From first dose of the study drug up to 30 days after the last dose (up to 21.7 months)
Part A2: Backfill: Number of Participants Exhibiting Overall Survival (OS)
OS was measured from the date of first dose until the date of death due to any cause.
Time frame: From first dose of the study drug up to 30 days after the last dose (up to 21.7 months)
Part A1: Dose Escalation: Maximum Plasma Concentration (Cmax) of TAS3351
Cmax is the maximum observed plasma concentration within the dosing interval. Blood samples for pharmacokinetic (PK) analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose; Cycle 1 Day 15: Pre-dose and at multiple timepoints up to 24 hours post dose
Part A1: Dose Escalation: Area Under The Plasma Concentration-Time Curve (AUC24) of TAS3351
AUC24 is the area under the curve from the time of dosing up to time 24hours. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose; Cycle 1 Day 15: Pre-dose and at multiple timepoints up to 24 hours post dose
Part A1: Dose Escalation: Area Under The Plasma Concentration-Time Curve (AUCinf) of TAS3351
AUCinf is the area under the plasma concentration-time curve from time of dosing extrapolated to infinity. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose
Part A1: Dose Escalation: Time To Maximum Plasma Concentration (Tmax) of TAS3351
Tmax is the time to maximum plasma concentration within the dosing interval. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose; Cycle 1 Day 15: Pre-dose and at multiple timepoints up to 24 hours post dose
Part A1: Dose Escalation: Terminal Elimination Half-Life (T½) of TAS3351
T1/2 is the terminal elimination half-life. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose
Part A1: Dose Escalation: Cmax of Metabolite TAS-05-14317
Cmax is the maximum observed plasma concentration within the dosing interval. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose; Cycle 1 Day 15: Pre-dose and at multiple timepoints up to 24 hours post dose
Part A1: Dose Escalation: AUC24 of Metabolite TAS-05-14317
AUC24 is the area under the curve from the time of dosing up to time 24hours. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose; Cycle 1 Day 15: Pre-dose and at multiple timepoints up to 24 hours post dose
Part A1: Dose Escalation: AUCinf of Metabolite TAS-05-14317
AUCinf is the area under the plasma concentration-time curve from time of dosing extrapolated to infinity. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose
Part A1: Dose Escalation: Tmax of Metabolite TAS-05-14317
Tmax is the time to maximum plasma concentration within the dosing interval. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose; Cycle 1 Day 15: Pre-dose and at multiple timepoints up to 24 hours post dose
Part A1: Dose Escalation: T½ of Metabolite TAS-05-14317
T1/2 is the terminal elimination half-life. Blood samples for PK analysis were collected at specified timepoints. A PK lead-in with a single TAS3351 dose on Cycle 1 Day -3, followed by PK sampling three days before the start of continuous daily dosing, was included to characterize the PK profile.
Time frame: Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose
Part B: Dose Expansion and Part C: Phase 2: Number of Participants With TEAEs
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; it did not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an AE that is starting or worsening at the time of or after the first dose of study drug administration and within 30 days after the last dose of study drug and did not necessarily have a causal relationship to the use of the study drug.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: DoR by ICR
DOR was calculated for all responders from the date of first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10 mm.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: PFS by ICR
PFS is the time from date of first dose to the date of documentation of disease progression, or date of death, whichever occurs first.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: DCR by ICR
DCR was the proportion of participants who achieved a CR, PR, or SD. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis \<10 mm. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referencing the smallest sum diameters while on study.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: ORR by Investigator Assessment
ORR was the proportion of participants experiencing a PR or CR according to RECIST v1.1 criteria. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10mm.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: DoR by Investigator Assessment
DOR was calculated for all responders from the date of first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10 mm.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: PFS by Investigator Assessment
PFS was defined as the time from date of first dose to the date of documentation of disease progression, or date of death, whichever occurred first.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: DCR by Investigator Assessment
DCR was the proportion of participants who achieved a CR, PR, or SD. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis \<10 mm. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referencing the smallest sum diameters while on study.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: Intracranial ORR (icORR) by Investigator Assessment
The icORR was defined as percentage of participants experiencing a PR or CR. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10mm. The icORR was planned to be assessed based on ORR of central nerve system (CNS) lesions only.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: Intracranial DoR (icDOR) by Investigator Assessment
The icDoR was planned to be calculated for all responders from the date of first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Evaluation of target lesions defined a CR as the disappearance of all target lesions and non-target lesions (if applicable), and normalization of tumor marker level; PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum of diameters for all target lesion assessments. Evaluation of non-target lesions was defined as the persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. For both target and non-target evaluations, any pathological lymph node must have had a reduction in short axis to \<10 mm. The icDoR was planned to be assessed based on DoR of CNS lesions only.
Time frame: Up to approximately 21.7 months
Part B: Dose Expansion and Part C: Phase 2: OS
OS was measured from the date of first dose until the date of death due to any cause.
Time frame: Up to approximately 21.7 months
Part C: Phase 2: Participant Reported Outcome Assessed by European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30)
The EORTC QLQ-C30 is a 30-item questionnaire meant to assess different aspects that define the quality of life of cancer participants and survivors. It facilitates insights into participants' physical, emotional, and social wellbeing, ultimately supporting more informed treatment decisions and care strategies. The questionnaire is divided into 4 parts, namely global health status/ quality of life, functional scales, symptom scales and single-item symptoms. Each item was meant to be scored on a scale of 1 (Not at all) to 4 (Very much). Scores obtained from each section are transformed to a 0-100 score. For the functional and global health status scales, higher scores indicate better functioning or quality of life. For symptom scales and single-item measures, higher scores indicate greater symptom severity.
Time frame: Up to approximately 21.7 months
Part C: Phase 2: Participant Reported Outcome Assessed by EuroQol 5D-5L Questionnaire
The EQ-5D-5L is a standardized, generic, participant-reported instrument developed by the EuroQol Group to assess health-related quality of life across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Participants were to rate five dimensions namely, mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item is scores on a score of 1 (no problems) to 5 (extreme problems). The combination of responses forms a 5-digit health state which is converted into a single utility index score using a country-specific value set. Higher utility scores indicate better health-related quality of life.
Time frame: Up to approximately 21.7 months