Carcinoma, Non-small Cell Lung
Conditions
Brief summary
The purpose of this study is to establish whether patients with malignancy harboring a discoidin domain receptor 2 mutation or an inactivating B-RAF mutation will respond to dasatinib.
Interventions
DRUGDasatinib
Tablet, oral, 140 mg, once daily until unacceptable toxicity or disease progression
Sponsors
Bristol-Myers Squibb
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
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria * Diagnosis of advanced malignancy, nonsmall-cell lung cancer (NSCLC) only during stage 1 of accrual. * Nonsynonymous mutation of B-RAF or DDR2, defined as follows:. i) NSCLC with inactivating B-RAF mutation. ii) NSCLC with discoidin domain receptor 2 (DDR2) mutation. iii) Malignancy of other histology with DDR2 mutation or inactivating B-RAF mutation, or NSCLC having a B-RAF mutation that is not functionally characterized. * At least 1 target lesion per Response Evaluation Criteria in Solid Tumors, vol 1.1, on baseline staging evaluation. * Disease progression after ≥ 1 prior treatment regimen.
Exclusion criteria
* Pleural or pericardial effusion, Grade \>1. * QTcF \>470 msec (Grade ≥2) or diagnosed congenital long QT syndrome. * Absolute granulocyte count \<1500/mm\^3. * Hemoglobin level \<10 g/dL. * Platelet count \< 75,000/mm\^3. * Serum calcium level \<institutional lower limit of normal. * Hypokalemia, hypophosphatemia, or hypomagnesemia, Grade \>1, despite supplementation. * Creatinine \>3\*institutional upper limit of normal (ULN). * Total bilirubin level \>1.5\*ULN. * Alanine transaminase level \>3\*ULN. * Other protocol-defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From enrollment of last patient to 24 months or until all patients have died, whichever occurs first | ORR is defined as the percentage of patients with best tumor response of either Partial Response (a 30% or greater decrease in the sum of the longest diameter \[LD\] of all lesions in reference to the baseline sum LD) or Complete Response (disappearance of clinical and radiologic evidence of target lesions), according to Response Evaluation Criteria in Solid Tumors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From enrollment of last patient to 24 months or until all patients have died, whichever occurs first | Overall survival is defined as the time from treatment start date to the date of death. If a patient does not die, survival will be censored on the last date the patient was known to be alive. |
| Progression-free Survival (PFS) Distribution | From Day 1 of study treatment to Week 12 | PFS distribution is defined as the percentage of patients with no documentation of disease progression at a specified time point. Confidence interval computed using the Brookmeyer and Crowley method |
| Duration of Response (DOR) | From enrollment of last patient to 24 months or until all patients have died, whichever occurs first | DOR is defined as the time from the first assessment documentation of partial response (PR) or complete response (CR) until the first assessment documentation of disease progression. |
| Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | From enrollment of last patient to 24 months or until all patients have died, whichever occurs first | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or unknown relationship to study drug. |
| Number of Participants With Laboratory Testing Results That Meet the Criteria for Grade 3 or 4 Abnormality | From enrollment of last patient to 24 months or until all patients have died, whichever occurs first | Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to adverse event. Laboratory values graded by Common Terminology Criteria for Adverse Events, volume 3. Hemoglobin, Grade 3: \<8.0 - 6.5 g/dL, \<4.9-4.0 mmol/L, \<80-65 g/L. Alkaline phosphatase, Grade 3: \>5.0-20.0\*upper limit of normal (ULN). Total bilirubin, Grade 3: \>3.0-10.0\*ULN. Calcium, low, Grade 3: \<7.0-6.0 mg/dL, \<1.75-1.5 mmol/L. |
| Progression-free Survival (PFS) | From Day 1 of study treatment to Week 12 | PFS is defined as the time from treatment start date to the earliest evidence of disease progression or death. Patients who die or whose disease does not progress will be censored on the date of their last tumor assessment. |
Countries
Brazil, Canada, Germany, Poland, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 19 patients were enrolled, and 14 received treatment in 2 cohorts: 9 with nonsmall-cell lung cancer (NSCLC) and an inactivating B-RAF mutation and 5 with NSCLC and a discoidin domain receptor 2 (DDR2) mutation.
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) Participants with nonsmall-cell lung cancer (NSCLC) and an inactivating B-RAF mutation received dasatinib, 140 mg, once daily as a tablet until unacceptable toxicity or disease progression occurred | 9 |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) Participants with NSCLC and a discoidin domain receptor 2 (DDR2) mutation received dasatinib, 140 mg, once daily as a tablet until unacceptable toxicity or disease progression occurred | 5 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease progression | 7 | 5 |
| Overall Study | Study drug toxicity | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 3 Participants |
| Age, Continuous | 66.5 Years | 63.0 Years | 67.0 Years |
| Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG score 0 | 2 Participants | 1 Participants | 1 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG score 1 | 9 Participants | 3 Participants | 6 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG score 2 | 3 Participants | 1 Participants | 2 Participants |
| Histopathologic Grade G2-moderately differentiated | 4 Participants | 2 Participants | 2 Participants |
| Histopathologic Grade G3-poorly differentiated | 2 Participants | 0 Participants | 2 Participants |
| Histopathologic Grade GX-grade cannot be assessed | 8 Participants | 3 Participants | 5 Participants |
| Nonsmall-cell lung carcinoma histology Adenocarcinoma | 8 Participants | 1 Participants | 7 Participants |
| Nonsmall-cell lung carcinoma histology Bronco-alveolar carcinoma | 1 Participants | 0 Participants | 1 Participants |
| Nonsmall-cell lung carcinoma histology Large cell carcinoma | 1 Participants | 0 Participants | 1 Participants |
| Nonsmall-cell lung carcinoma histology Squamous cell carcinoma | 4 Participants | 4 Participants | 0 Participants |
| Number of Index Lesions 1 | 3 Participants | 1 Participants | 2 Participants |
| Number of Index Lesions 2 | 2 Participants | 2 Participants | 0 Participants |
| Number of Index Lesions 3 | 5 Participants | 1 Participants | 4 Participants |
| Number of Index Lesions 4 | 4 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 10 Participants | 5 Participants | 5 Participants |
| Race/Ethnicity, Customized Not reported | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Female | 6 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 4 Participants |
| Time from cancer diagnosis to start of study therapy | 12.1 Months | 8.5 Months | 14.4 Months |
| Tumor Type Nonsmall-cell lung carcinoma | 14 Participants | 5 Participants | 9 Participants |
| Tumor Type Other | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 14 |
| serious Total, serious adverse events | 11 / 14 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR is defined as the percentage of patients with best tumor response of either Partial Response (a 30% or greater decrease in the sum of the longest diameter \[LD\] of all lesions in reference to the baseline sum LD) or Complete Response (disappearance of clinical and radiologic evidence of target lesions), according to Response Evaluation Criteria in Solid Tumors.
Time frame: From enrollment of last patient to 24 months or until all patients have died, whichever occurs first
Population: All participants who received at least 1 dose of study drug. Because no patients had a response of CR or PR, ORR could not be calculated.
Secondary
Duration of Response (DOR)
DOR is defined as the time from the first assessment documentation of partial response (PR) or complete response (CR) until the first assessment documentation of disease progression.
Time frame: From enrollment of last patient to 24 months or until all patients have died, whichever occurs first
Population: All participants who received at least 1 dose of study drug. Because no patients had a response of CR or PR, DOR could not be calculated.
Secondary
Number of Participants With Laboratory Testing Results That Meet the Criteria for Grade 3 or 4 Abnormality
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to adverse event. Laboratory values graded by Common Terminology Criteria for Adverse Events, volume 3. Hemoglobin, Grade 3: \<8.0 - 6.5 g/dL, \<4.9-4.0 mmol/L, \<80-65 g/L. Alkaline phosphatase, Grade 3: \>5.0-20.0\*upper limit of normal (ULN). Total bilirubin, Grade 3: \>3.0-10.0\*ULN. Calcium, low, Grade 3: \<7.0-6.0 mg/dL, \<1.75-1.5 mmol/L.
Time frame: From enrollment of last patient to 24 months or until all patients have died, whichever occurs first
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Participants With Laboratory Testing Results That Meet the Criteria for Grade 3 or 4 Abnormality | Alkaline phosphatase, Grade 3 | 1 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Participants With Laboratory Testing Results That Meet the Criteria for Grade 3 or 4 Abnormality | Hemoglobin, Grade 3 | 2 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Participants With Laboratory Testing Results That Meet the Criteria for Grade 3 or 4 Abnormality | Total bilirubin, Grade 3 | 1 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Participants With Laboratory Testing Results That Meet the Criteria for Grade 3 or 4 Abnormality | Calcium, low, Grade 3 | 1 Participants |
Secondary
Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or unknown relationship to study drug.
Time frame: From enrollment of last patient to 24 months or until all patients have died, whichever occurs first
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | SAEs | 7 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | AEs leading to discontinuation | 7 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Death within 30 days of last treatment | 3 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Drug-related AEs leading to discontinuation | 2 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Drug-related SAEs | 0 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Drug-related AEs | 6 Participants |
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Death | 8 Participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Drug-related AEs | 3 Participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Death | 4 Participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Death within 30 days of last treatment | 1 Participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | SAEs | 4 Participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Drug-related SAEs | 1 Participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | AEs leading to discontinuation | 2 Participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Number of Patients With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation | Drug-related AEs leading to discontinuation | 0 Participants |
Secondary
Overall Survival
Overall survival is defined as the time from treatment start date to the date of death. If a patient does not die, survival will be censored on the last date the patient was known to be alive.
Time frame: From enrollment of last patient to 24 months or until all patients have died, whichever occurs first
Population: All participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Overall Survival | 3.06 Months |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Overall Survival | 4.21 Months |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from treatment start date to the earliest evidence of disease progression or death. Patients who die or whose disease does not progress will be censored on the date of their last tumor assessment.
Time frame: From Day 1 of study treatment to Week 12
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Progression-free Survival (PFS) | 1.41 Months |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Progression-free Survival (PFS) | 1.38 Months |
Secondary
Progression-free Survival (PFS) Distribution
PFS distribution is defined as the percentage of patients with no documentation of disease progression at a specified time point. Confidence interval computed using the Brookmeyer and Crowley method
Time frame: From Day 1 of study treatment to Week 12
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib, 140 mg (NSCLC With Inactivating B-RAF Mutation) | Progression-free Survival (PFS) Distribution | 1.41 Percentage of participants |
| Dasatinib, 140 mg (NSCLC With DDR2 Mutation) | Progression-free Survival (PFS) Distribution | 1.38 Percentage of participants |