Advanced or Metastatic Non-small Cell Lung Cancer
Conditions
Keywords
NSCLC, phase 2 study, TAS-114, S-1
Brief summary
This is a randomized, open-label, Phase 2 study of TAS-114 administered in combination with S-1, to investigate the efficacy, safety and tolerability of the TAS-114/S-1 regimen in patients with advanced or metastatic NSCLC. The study will be conducted internationally in 2 regions: Asian \[Japan\] and Western \[Europe and US\]. Patients will be randomized into TAS-114/S-1 arm versus S-1 control arm in a 1:1 ratio.
Detailed description
Randomization will take place once the consented patient has completed all the necessary baseline procedures and is deemed eligible for study entry. Treatment assignment will be done centrally using a dynamic allocation method (biased coin) via an interactive voice/web response system (IXRS) stratified by: * Geographical region (Region 1: Asian \[Japan\]; Region 2: Western \[Europe and US\]) * Histological subtypes (nonsquamous cell carcinoma \[including mixed\] and squamous cell carcinoma)
Interventions
DRUGTAS-114
TAS-114 was a modulator of 5-fluorouracil (5-FU).
DRUGS-1
S-1 was designed to provide oral delivery of 5-FU and to reduce the rate of degradation of 5-FU in vivo.
Sponsors
Taiho Oncology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years old (≥ 20 years old in Japan); 2. Histologically diagnosed or cytologically proven advanced or metastatic NSCLC patients, either Stage IIIB/Stage IV disease (according to Version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology), or recurrent disease following radiation therapy or surgical resection; 3. Patients who had received at least 2 prior therapies for advanced or metastatic disease condition, including platinum doublet and pemetrexed, docetaxel, or immunotherapy, and were refractory to or unable to tolerate their last prior therapy 4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1, 2009); 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; 6. Predicted life expectancy of at least 3 months; 7. Able to take medications orally; 8. Adequate organ function 9. Women of childbearing potential (WOCBP) must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to the first dose and for 6 months after the last dose) if conception is possible during this interval. 10. Willing and able to comply with required scheduled visits and study procedures.
Exclusion criteria
1. Treatment with any of the following within the specified time frame prior to the study drug administration: * Major surgery within prior 4 weeks and minor surgery within 7 days; * Radiotherapy for extended field within prior 4 weeks or limited field within prior 2 weeks; * Any anticancer therapy or investigational agent within prior 3 weeks. 2. A serious illness or medical condition 3. Concomitant treatment with the following drugs that may interact with S-1: Sorivudine, brivudine, uracil, eniluracil, folinate/folinic acid, Cimetidine, dipyridamole, and nitroimidazoles, including metronidazole and misonidazoleMethotrexate, Clozapine,Allopurinol,Phenytoin,Flucytosine, a fluorinated pyrimidine antifungal agent,Coumarin-derivative anticoagulant 4. Known hypersensitivity to S-1 or its metabolites (eg, 5-FU); 5. Previous use of TAS-114, S-1, and 5-FU drugs; 6. A pregnant or lactating female or possibly pregnant women, or men or women wishing to have children during the study period; 7. A judgment of the investigator that the patient is inappropriate for study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Based on Central Independent Review | From date of randomization or until date of disease progression or death whichever occurred first (approximately up to 13 months) | Progression-free survival was defined as the time (in months) from the day of randomization to the start of radiologic disease progression or death (any cause), whichever occurred first. Response assessments were made based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). As per RECIST 1.1 criteria, progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). (Note: the appearance of one or more new lesions was also considered progressions). Participants who did not have disease progression or died were censored at the last known time that the participant was progression free. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From date of randomization until death (approximately up to 15 months) | OS was defined as the time from the first dose of the study treatment to death from any cause. Participants who were alive at the end of study were censored at the last date the participant was known to be alive. OS was estimated from Kaplan-Meier method. |
| Overall Response Rate (ORR) Based on Central Independent Review | From date of first dose of study drug to the date of first documentation of progression or death (approximately up to 13 months) | ORR was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR) per response evaluation criteria in solid tumors (RECIST) version 1.1. CR was defined as the disappearance of all target lesions and non-target lesions and normalization of tumor marker level. Any pathological and non-pathological lymph nodes must have reduction in short axis to less than (\<) 10 mm. 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 diameters. |
| Disease Control Rate (DCR) Based on Central Independent Review | From date of first dose of study drug to the date of first documentation of progression or death (approximately up to 13 months) | DCR was defined as the percentage of participants with objective evidence CR, PR, or stable disease (SD). Based on the central review of tumor assessments per RECIST, version 1.1. CR was defined as disappearance of all target lesions. Reduction in any pathological lymph nodes in short axis to \<10 mm. 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 diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum diameters during study. |
| Duration of Response (DR) Based on Central Independent Review | From date of first response to the date of first documentation of progression or death (approximately up to 13 months) | DR was derived for participants with objective evidence of PR or CR. DR was defined as the time (in months) from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause. Participants who were alive and progression-free as of the analysis cut-off date were censored at their last evaluable tumor response assessment before initiation of any new anticancer treatment. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From first dose of study drug up to 30 days after the last dose of study drug (approximately up to 13 months) | An adverse event (AE) was defined as any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily have a causal relationship with the use of the study treatment. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as AEs that developed or worsened during the TEAE period which was defined as the period from the time of first dose of study treatment until 30 days after last dose of study treatment. AEs included both serious and non- serious adverse events. |
Countries
France, Italy, Japan, Poland, Spain, United States
Participant flow
Recruitment details
The study was conducted at 26 centers in 5 countries.
Pre-assignment details
A total of 128 participants were randomized.1 participant in S-1 (Monotherapy) arm was randomized but not treated.
Participants by arm
| Arm | Count |
|---|---|
| TAS-114 + S-1 Participants received 400 mg of TAS-114 tablets orally BID along with 30 mg/m\^2 of S-1 capsule BID for 2 weeks (Day 1 to 14), followed by 1 week recovery period (Day 15 to 21) in each 21 days cycle, until progressive disease (PD), occurrence of intolerable side effects, removal by the Investigator, or withdrawal of consent (maximum treatment duration: 51 weeks). | 64 |
| S-1 (Monotherapy) Participants received 30 mg/m\^2 of S-1 capsules BID for 2 weeks (Day 1 to 14) followed by 1 week recovery period (Day 15 to 21) in each 21 days cycle, until progressive disease (PD), occurrence of intolerable side effects, removal by the Investigator, or withdrawal of consent (maximum treatment duration: 38 weeks). | 64 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 7 |
| Overall Study | Clinical Disease Progression | 5 | 4 |
| Overall Study | On Treatment | 9 | 11 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Radiologic Disease Progression | 36 | 39 |
| Overall Study | Randomized but not treated | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | S-1 (Monotherapy) | Total | TAS-114 + S-1 |
|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 10.22 | 63.2 years STANDARD_DEVIATION 9.06 | 63.8 years STANDARD_DEVIATION 7.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 13 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 92 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants | 23 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 30 Participants | 60 Participants | 30 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 26 Participants | 13 Participants |
| Race (NIH/OMB) White | 21 Participants | 42 Participants | 21 Participants |
| Sex: Female, Male Female | 16 Participants | 39 Participants | 23 Participants |
| Sex: Female, Male Male | 48 Participants | 89 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 36 / 64 | 29 / 63 |
| other Total, other adverse events | 64 / 64 | 61 / 63 |
| serious Total, serious adverse events | 30 / 64 | 19 / 63 |
Outcome results
Primary
Progression-free Survival (PFS) Based on Central Independent Review
Progression-free survival was defined as the time (in months) from the day of randomization to the start of radiologic disease progression or death (any cause), whichever occurred first. Response assessments were made based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). As per RECIST 1.1 criteria, progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). (Note: the appearance of one or more new lesions was also considered progressions). Participants who did not have disease progression or died were censored at the last known time that the participant was progression free.
Time frame: From date of randomization or until date of disease progression or death whichever occurred first (approximately up to 13 months)
Population: Intent-to-Treat (ITT) population included all participants randomized in the study, regardless of whether they actually received any study treatment (TAS-114 or S-1) or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAS-114 + S-1 | Progression-free Survival (PFS) Based on Central Independent Review | 3.65 months |
| S-1 (Monotherapy) | Progression-free Survival (PFS) Based on Central Independent Review | 4.17 months |
p-value: 0.274495% CI: [0.71, 1.88]Log Rank
Secondary
Disease Control Rate (DCR) Based on Central Independent Review
DCR was defined as the percentage of participants with objective evidence CR, PR, or stable disease (SD). Based on the central review of tumor assessments per RECIST, version 1.1. CR was defined as disappearance of all target lesions. Reduction in any pathological lymph nodes in short axis to \<10 mm. 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 diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum diameters during study.
Time frame: From date of first dose of study drug to the date of first documentation of progression or death (approximately up to 13 months)
Population: TR population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAS-114 + S-1 | Disease Control Rate (DCR) Based on Central Independent Review | 80.3 percentage of participants |
| S-1 (Monotherapy) | Disease Control Rate (DCR) Based on Central Independent Review | 75.9 percentage of participants |
Secondary
Duration of Response (DR) Based on Central Independent Review
DR was derived for participants with objective evidence of PR or CR. DR was defined as the time (in months) from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause. Participants who were alive and progression-free as of the analysis cut-off date were censored at their last evaluable tumor response assessment before initiation of any new anticancer treatment.
Time frame: From date of first response to the date of first documentation of progression or death (approximately up to 13 months)
Population: TR population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAS-114 + S-1 | Duration of Response (DR) Based on Central Independent Review | 3.38 months |
| S-1 (Monotherapy) | Duration of Response (DR) Based on Central Independent Review | NA months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
An adverse event (AE) was defined as any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily have a causal relationship with the use of the study treatment. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as AEs that developed or worsened during the TEAE period which was defined as the period from the time of first dose of study treatment until 30 days after last dose of study treatment. AEs included both serious and non- serious adverse events.
Time frame: From first dose of study drug up to 30 days after the last dose of study drug (approximately up to 13 months)
Population: Analysis was performed on As-Treated (AT) population which included all participants who received at least 1 dose of TAS-114 or S-1.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TAS-114 + S-1 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 64 Participants |
| TAS-114 + S-1 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 30 Participants |
| S-1 (Monotherapy) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 61 Participants |
| S-1 (Monotherapy) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 19 Participants |
Secondary
Overall Response Rate (ORR) Based on Central Independent Review
ORR was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR) per response evaluation criteria in solid tumors (RECIST) version 1.1. CR was defined as the disappearance of all target lesions and non-target lesions and normalization of tumor marker level. Any pathological and non-pathological lymph nodes must have reduction in short axis to less than (\<) 10 mm. 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 diameters.
Time frame: From date of first dose of study drug to the date of first documentation of progression or death (approximately up to 13 months)
Population: Tumor response (TR) population included all participants randomized in the study, regardless of whether they actually received any study treatment (TAS-114 or S-1) or not; with measurable disease (at least one target lesion) at baseline and with at least one tumor evaluation (participants who had disease progression or had a cancer related death prior to their 1st tumor evaluation were also considered evaluable).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAS-114 + S-1 | Overall Response Rate (ORR) Based on Central Independent Review | 19.7 percentage of participants |
| S-1 (Monotherapy) | Overall Response Rate (ORR) Based on Central Independent Review | 10.3 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the first dose of the study treatment to death from any cause. Participants who were alive at the end of study were censored at the last date the participant was known to be alive. OS was estimated from Kaplan-Meier method.
Time frame: From date of randomization until death (approximately up to 15 months)
Population: ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAS-114 + S-1 | Overall Survival (OS) | 7.92 months |
| S-1 (Monotherapy) | Overall Survival (OS) | 9.82 months |
p-value: 0.143195% CI: [0.8, 2.14]Log Rank