Non Small Cell Lung Cancer
Conditions
Keywords
NSCLC, Stage IV, Pemetrexed, Dacomitinib
Brief summary
To identify a dose of dacomitinib in combination with pemetrexed that is safe and tolerated as determined by the incidence of DLTs (dose limiting toxicities).
Detailed description
This open label phase Ib trial aims to determine the safety, tolerability, the pharmacokinetic profile, and to identify a dose of dacomitinib in combination with pemetrexed. Three sites in Austria will participate in this study. Six to nine patients will initially be enrolled to receive the target dose of 45 mg qd dacomitinib (starting from day 2 of first cycle) in combination with pemetrexed (500 mg/m² 10 min infusion, once every 3 weeks). One cycle is defined as 21 days. The first 3 subjects will be enrolled at a rate of ≤ 1 subject per week. If the target dose regimen is safe based on the incidence of DLT another 3 subjects will be enrolled. If the dose of 45 mg qd is not safe alternate lower doses will be explored (dose level -1, dose level -2) to identify the maximal tolerated dose (MTD) of dacomitinib in combination of pemetrexed. Six to nine patients per dose level will be enrolled.
Interventions
DRUGDacomitinib, Pemetrexed
Pemetrexed 500mg/m2 i.v (q21d) Dacomitinib 45mg orally (continuous)
Sponsors
Central European Cooperative Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Histologically or cytologically confirmed stage IV non-squamous NSCLC * Patients who are candidates to receive pemetrexed monotherapy * If pemetrexed has been administered as first line therapy there must be a treatment free interval of at least one cycle (21 days) * Measurable disease by RECIST criteria version 1.1. * ≥18 years of age * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 * Adequate left ventricular ejection fraction (LVEF) ≥ 50% by either echocardiogram or multigated acquisition scan (MUGA) * Adequate organ function, including: 1. Adequate bone marrow reserve: absolute neutrophil count (ANC) should be ≥ 1500 cells/mm3, platelets should be ≥ 100.000 cells/mm3 2. Creatinine clearance ≥ 45 mL/min 3. Total bilirubin ≤ 1.5 x upper normal limit (ULN) 4. Aspartate Aminotransferase (AST) (SGOT) ≤ 3 x ULN (≤ 5.0 x ULN if hepatic metastases) 5. Alanine Aminotransferase (ALT) (SGPT) ≤ 3 x ULN (≤ 5.0 x ULN if hepatic metastases) * Female patients or their partners must be postmenopausal (defined as 12 months of amenorrhea following last menses), surgically sterile or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter (the definition of effective contraception will be based on the judgment of the investigator). Male patients or their partners must be surgically sterile or must agree to use a barrier method of contraception while receiving trial treatment and for at least 3 months thereafter. (In all cases the definition of effective contraception will be based on the judgment of the investigator). * Able to comply with required protocol procedures and able to receive oral medications
Exclusion criteria
* Any evidence of mixed histology that includes elements of small cell or carcinoid lung cancer * Predominantly squamous cell histology * Patients with symptomatic brain metastases * Chemotherapy, radiotherapy, biological or investigational agents within two weeks of baseline disease assessments * Patients with uncontrolled or significant cardiovascular disease, including: 1. Myocardial infarction within 12 months 2. Uncontrolled angina within 6 months 3. Congestive heart failure within 6 months 4. Diagnosed or suspected congenital long QT syndrome 5. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) 6. Prolonged QTc interval on pre-entry electrocardiogram. QTc must be less than CTC Grade 2 (≤480 msec) using appropriate correction formula with manual read by investigator if required. The echocardiogram (ECG) may be repeated for evaluation of eligibility after management of correctable causes for observed QTc prolongation 7. Any history of second or third degree heart block (may be eligible if currently have a pacemaker) 8. Heart rate \<50/minute on baseline electrocardiogram 9. Uncontrolled hypertension * Prior malignancy: Patients will not be eligible if they have evidence of other malignancy (other than non-melanoma skin cancer or in situ cervical cancer, or localized and presumed cured prostate cancer with prostate specific antigen (PSA) \< ULN) within the last 3 years. * Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start. Known hypersensitivity to pemetrexed and/or dacomitinib * Patients with exposure to other investigational drug therapy * Previous therapy with an oral tyrosine kinase inhibitor (TKI)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (DLTs) | From start of treatment to end of treatment or death, whichever occurs first. The study was suspended after 36 months. | The primary objective of this study is to determine the maximal tolerated dose (MTD) of the combination pemetrexed + dacomitinib by the incidence of dose limiting toxicities (DLTs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Until progression of disease (PD) or 24 month after end of treatment for participants with no PD. The study was suspended after 36 months | Overall Response Rate (ORR) is defined as the proportion of patients with complete Response (CR) or partial Response (PR). |
| Overall Survival | until date of death. The study was suspended after 36 months. | Overall survival (OS) defined as time from start of Dacomitinib to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. Patients were followed up for survival for 24 month after end of Treatment. |
| Progression-free Survival | Up to progression or death due to any cause. The study was suspended after 36 months | Progression-free survival (PFS) defined as time from start of Dacomitinib to date of progression or date of death from any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients were followed up for progression-free survival for 24 month after end of Treatment. |
Countries
Austria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dacomitinib, Pemetrexed Pemetrexed 500mg/m2 (i.v) q21d Dacomitinib 45mg/ orally (continuous)
Dacomitinib, Pemetrexed: Pemetrexed 500mg/m2 i.v (q21d) Dacomitinib 45mg orally (continuous) | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Dacomitinib, Pemetrexed |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 58.0 years STANDARD_DEVIATION 11.14 |
| Body Surface Area (BSA) | 1.9 m² STANDARD_DEVIATION 0.2 |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 | 4 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 | 1 Participants |
| Electrocardiogram (ECG) results Abnormal | 1 Participants |
| Electrocardiogram (ECG) results Normal | 4 Participants |
| Epidermal growth factor receptor (EGFR) mutation status Negative | 1 Participants |
| Epidermal growth factor receptor (EGFR) mutation status Not determined | 4 Participants |
| Heart rate | 70.6 bpm STANDARD_DEVIATION 8.62 |
| Height | 176.4 cm STANDARD_DEVIATION 14.26 |
| KRAS status Negative | 1 Participants |
| KRAS status Not determined | 4 Participants |
| Left Ventricular Ejection Fraction (LVEF) | 65.2 percent STANDARD_DEVIATION 12.28 |
| Prior antibody therapy No | 5 Participants |
| Prior antibody therapy Yes | 0 Participants |
| Prior chemotherapy No | 0 Participants |
| Prior chemotherapy Yes | 5 Participants |
| Prior radiotherapy No | 5 Participants |
| Prior radiotherapy Yes | 0 Participants |
| Prior surgery No | 0 Participants |
| Prior surgery Yes | 5 Participants |
| Race/Ethnicity, Customized White/ Caucasian | 5 Participants |
| Region of Enrollment Austria | 5 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
| Stage at primary diagnosis: Distant metastasis (M) M0 | 1 Participants |
| Stage at primary diagnosis: Distant metastasis (M) M1 | 4 Participants |
| Stage at primary diagnosis: Primary tumor (T) T0 | 1 Participants |
| Stage at primary diagnosis: Primary tumor (T) T1b | 1 Participants |
| Stage at primary diagnosis: Primary tumor (T) T2a | 2 Participants |
| Stage at primary diagnosis: Primary tumor (T) T4 | 1 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) N0 | 2 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) N2 | 2 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) N3 | 1 Participants |
| Temperature | 36.4 °C |
| Weight | 73.8 kg STANDARD_DEVIATION 9.68 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 4 / 5 |
Outcome results
Primary
Dose Limiting Toxicities (DLTs)
The primary objective of this study is to determine the maximal tolerated dose (MTD) of the combination pemetrexed + dacomitinib by the incidence of dose limiting toxicities (DLTs).
Time frame: From start of treatment to end of treatment or death, whichever occurs first. The study was suspended after 36 months.
Population: All enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dacomitinib, Pemetrexed | Dose Limiting Toxicities (DLTs) | 40 percentage of participants |
Secondary
Overall Response Rate
Overall Response Rate (ORR) is defined as the proportion of patients with complete Response (CR) or partial Response (PR).
Time frame: Until progression of disease (PD) or 24 month after end of treatment for participants with no PD. The study was suspended after 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dacomitinib, Pemetrexed | Overall Response Rate | 0 percentage of participants |
Secondary
Overall Survival
Overall survival (OS) defined as time from start of Dacomitinib to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. Patients were followed up for survival for 24 month after end of Treatment.
Time frame: until date of death. The study was suspended after 36 months.
Population: All enrolled participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dacomitinib, Pemetrexed | Overall Survival | 9.6 months |
Secondary
Progression-free Survival
Progression-free survival (PFS) defined as time from start of Dacomitinib to date of progression or date of death from any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients were followed up for progression-free survival for 24 month after end of Treatment.
Time frame: Up to progression or death due to any cause. The study was suspended after 36 months
Population: All enrolled participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dacomitinib, Pemetrexed | Progression-free Survival | 4.7 months |