Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Cancer, NSCLC, EGFR mutation, C797S mutation, TAS3351
Brief summary
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.
Detailed description
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.
Interventions
DRUGTAS3351
Oral tablets.
Sponsors
Taiho Oncology, 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
* Locally advanced, non-resectable or metastatic NSCLC * Have adequate organ function * Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale * Has tumor tissue available to allow for analysis of EGFRmt status Dose Escalation: • Has any EGFRmt status Dose Escalation back-fill part, Dose Expansion and Phase II: * Has any sensitizing EGFRmt and a confirmed C797S EGFRmt * Has measurable disease per response evaluation criteria in solid tumors, version 1.1 (RECIST v1.1)
Exclusion criteria
* Participating in medical research not compatible with this study * Symptomatic and unstable central nervous system (CNS) metastases * Have not recovered from prior cancer treatment * Have a significant cardiac condition * Are a pregnant or breastfeeding female * A serious illness or medical condition * Unable to swallow or digest pills
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A1: Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (cycle length = 21 days) | 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. |
| Part B: Dose Expansion: Percentage of Participants With Objective Response Rate (ORR) by Independent Central Review (ICR) | Up to 21.7 months | 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). |
| Part C: Phase 2: Percentage of Participants With ORR by ICR | Up to approximately 21.7 months | 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. |
| Part A1: Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAE) | From first dose of the study drug up to 30 days after last dose (up to 21.7 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Dose Expansion and Part C: Phase 2: PFS by Investigator Assessment | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: DCR by Investigator Assessment | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: Intracranial ORR (icORR) by Investigator Assessment | Up to approximately 21.7 months | 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. |
| Part A1: Dose Escalation: Percentage of Participants With ORR | From first dose of the study drug up to 30 days after the last dose (up to approximately 21.7 months) | 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. |
| Part A1: Dose Escalation: Duration of Response (DoR) | From first dose of the study drug up to 30 days after the last dose (up to approximately 21.7 months) | 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. |
| Part A1: Dose Escalation: Percentage of Participants Exhibiting Disease Control Rate (DCR) | From first dose of the study drug up to 30 days after the last dose (up to approximately 21.7 months) | 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. |
| Part A2: Backfill: Number of Participants Exhibiting Progression Free Survival (PFS) | From first dose of the study drug up to 30 days after the last dose (up to 21.7 months) | 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. |
| Part A2: Backfill: Number of Participants Exhibiting Overall Survival (OS) | From first dose of the study drug up to 30 days after the last dose (up to 21.7 months) | OS was measured from the date of first dose until the date of death due to any cause. |
| Part A1: Dose Escalation: Maximum Plasma Concentration (Cmax) of TAS3351 | 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 | 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. |
| Part A1: Dose Escalation: Area Under The Plasma Concentration-Time Curve (AUC24) of TAS3351 | 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 | 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. |
| Part A1: Dose Escalation: Area Under The Plasma Concentration-Time Curve (AUCinf) of TAS3351 | Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose | 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. |
| Part A1: Dose Escalation: Time To Maximum Plasma Concentration (Tmax) of TAS3351 | 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 | 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. |
| Part A1: Dose Escalation: Terminal Elimination Half-Life (T½) of TAS3351 | Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose | 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. |
| Part A1: Dose Escalation: Cmax of Metabolite TAS-05-14317 | 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 | 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. |
| Part A1: Dose Escalation: AUC24 of Metabolite TAS-05-14317 | 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 | 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. |
| Part A1: Dose Escalation: AUCinf of Metabolite TAS-05-14317 | Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose | 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. |
| Part A1: Dose Escalation: Tmax of Metabolite TAS-05-14317 | 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 | 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. |
| Part A1: Dose Escalation: T½ of Metabolite TAS-05-14317 | Cycle 1 Day -3: Pre-dose and at multiple timepoints up to 72 hours post dose | 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. |
| Part B: Dose Expansion and Part C: Phase 2: Number of Participants With TEAEs | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: DoR by ICR | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: Intracranial DoR (icDOR) by Investigator Assessment | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: OS | Up to approximately 21.7 months | OS was measured from the date of first dose until the date of death due to any cause. |
| 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) | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: PFS by ICR | Up to approximately 21.7 months | PFS is the time from date of first dose to the date of documentation of disease progression, or date of death, whichever occurs first. |
| Part C: Phase 2: Participant Reported Outcome Assessed by EuroQol 5D-5L Questionnaire | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: DCR by ICR | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: ORR by Investigator Assessment | Up to approximately 21.7 months | 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. |
| Part B: Dose Expansion and Part C: Phase 2: DoR by Investigator Assessment | Up to approximately 21.7 months | 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. |
Countries
France, Germany, Japan, Netherlands, United States
Participant flow
Recruitment details
Participants took part in the study from 25 May 2023 to 14 March 2025.
Pre-assignment details
A total of 18 participants received at least one dose of TAS3351 in Part A1. The study was originally designed to be conducted in three parts: Phase 1: Part A (including Part A1: Dose Escalation and Part A2: Backfill) and Part B (Dose Expansion); Part C (Phase 2). However, as the study was terminated early, no participants were further enrolled in Parts A1 dose expansion for 700 milligrams (mg), A2, B, or C of the study and these parts were not conducted.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 12.28 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 2 / 3 | 3 / 3 | 3 / 3 | 4 / 5 | 3 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 3 | 0 / 5 | 0 / 4 |
Outcome results
None listed