Neoplasms
Conditions
Brief summary
This Phase I study will investigate the safety of BIBW 2992 in combination with standard dose pemetrexed (500mg/m2) given on a 21 day cycle in patients with advanced solid cancers. BIBW 2992 will be given on two different dose schedules; dosing on days 1-21 and dosing on days 1 to 6 of a 21 day cycle. The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), including BIBW 2992 have demonstrated efficacy in solid tumors including non-small cell lung cancer (NSCLC). In addition, pemetrexed has demonstrated efficacy and has been approved as single agent chemotherapy in second-line NSCLC patients with adenocarcinoma. The data obtained from this trial shall allow for a conclusion as to whether BIBW 2992 may be safely administered in advanced cancer patients in combination therapy with pemetrexed.
Interventions
DRUGBIBW 2992 low dose
patient receives low dose BIBW 2992 po daily on day 1 of 21 day cycle
DRUGBIBW 2992 high dose
patient receives high dose BIBW 2992 po daily on day 1 of 21 day cycle
DRUGpemetrexed
given intravenously on day 1 of a 21 day cycle
DRUGBIBW 2992 high dose 6 day
patient receives high dose BIBW 2992 po daily on days 1-6 on 1 of 21 day cycle
DRUGBIBW 2992 low dose 6 day
patient receives low dose BIBW 2992 po daily on days 1-6 on day 1 of 21 day cycle
DRUGBIBW 2992 medium dose 6 day
patient receives medium dose BIBW 2992 po daily on day1 to 6 of a 21 day cycle
DRUGBIBW 2992 medium dose
patient receives medium dose BIBW 2992 po daily on day 1 of 21 day cycle
Sponsors
Boehringer Ingelheim
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
1. Age 18 or older. 2. Eastern cooperative oncology group performance status of 0-2. 3. Life expectancy of at least 12 weeks. 4. Measurable disease according to Response evaluation criteria in solid tumors 1.1 criteria. 5. Written informed consent
Exclusion criteria
1. Treatment with an investigational drug within the past 28 days prior to the start of therapy 2. Persisting toxicities which are clinically significant from previous therapy 3. Patients who are unwilling or unable to take folic acid and vitamin B12 supplementation 4. Active brain metastases 5. Other active malignancy diagnosed within the past 3 years 6. Concomitant intercurrent illnesses that would limit compliance with trial requirement 7. Patients unable or unwilling to interrupt concomitant administration of Non-steroidal anti-inflammatory drugs (NSAIDS) as per pemetrexed prescribing information 8. Patients who have received prior therapy with BIBW 2992 9. Left ventricular function by echocardiogram or Multiple gated acquisition scan (MUGA) less than institutional lower limit of normal 10. Absolute neutrophil count (ANC) less than 1,500/mm3 11. Platelet count less than 100,000/mm3 12. Hemoglobin less than 90g/L 13. Total bilirubin less than 26µmol/L 14. Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) greater than 2.5 X ULN, except in case of known liver metastasis where maximum 5 X ULN is acceptable 15. Serum creatinine level greater than 133µmol/L and/or creatinine clearance (measured or calculated) less than 45 ml/min 16. History or recent gastrointestinal bleeding, obstruction or perforation or malabsorption syndrome and must be able to swallow the BIBW 2992 in whole by mouth. 17. History of interstitial lung disease 18. Women and men who are sexually active and unwilling to use a medically acceptable method of contraception 19. Pregnancy or breast feeding 20. Known or suspected active alcohol or drug abuse 21. Patients unable to comply with the protocol 22. Has a diagnosis of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). 23. Any known hypersensitivity to the trial drugs or their excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator Defined Dose Limiting Toxicity (DLT) During First Course of Treatment, Treated Set | DLT were assessed during the first cycle (days 1-21) | Occurence of DLT during the first course of treatment to determine the maximum tolerated dose (MTD) of Afatinib at two different dose schedules in combination with the standard established dose of pemetrexed (500 mg/m2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator Defined Dose Limiting Toxicity (DLT) During All Courses of Treatment, Treated Set | DLT were assessed during all cycles of treatment | Occurence of DLT during all courses of treatment with Afatinib at two different dose schedules in combination with the standard established dose of pemetrexed (500 mg/m2). |
| Objective Response (OR) | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression | Objective Response is defined as complete response or partial response according to the response evaluation criteria in solid tumours (RECIST) version 1.1. Complete Response (CR): disappearance of all non-target lesions and normalization of tumor marker level; Partial Response (PR): at least 30% decrease of the sum of longest diameter (LD) of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of LD of target lesions together with an absolute increase in the sum of LD of at least 5 millimeters; Stable Disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD. |
| Disease Control | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression | Disease Control is defined as complete response, partial response, or stable disease according to the response evaluation criteria in solid tumours (RECIST) version 1.1. |
| Progression Free Survival (PFS) | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression | PFS was defined as the time from the first treatment to the occurence of tumour progression or death, whichever came first. It was assessed according to RECIST version 1.1 criteria. |
| Tumour Shrinkage | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression | Tumour shrinkage is defined as the maximum percentage decrease from baseline in the sum of the longest diameters of target lesions. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Continuous Afatinib 30 mg Continuous Afatinib 30 mg plus Pemetrexed | 20 |
| Continuous Afatinib 40 mg Continuous Afatinib 40 mg plus Pemetrexed | 3 |
| Pulsed Afatinib 50 mg Pulsed Afatinib 50 mg plus Pemetrexed | 7 |
| Pulsed Afatinib 60 mg Pulsed Afatinib 60 mg plus Pemetrexed | 17 |
| Pulsed Afatinib 70 mg Pulsed Afatinib 70 mg plus Pemetrexed | 6 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 | 2 | 0 | 0 |
| Overall Study | Dose Limiting Toxicity (DLT) | 1 | 0 | 0 | 0 | 2 |
| Overall Study | Other Reason Not Defined Above | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Progressive disease | 13 | 2 | 5 | 15 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Continuous Afatinib 30 mg | Continuous Afatinib 40 mg | Pulsed Afatinib 50 mg | Pulsed Afatinib 60 mg | Pulsed Afatinib 70 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 60.2 years STANDARD_DEVIATION 9.4 | 53.7 years STANDARD_DEVIATION 16.6 | 69.6 years STANDARD_DEVIATION 10.5 | 57.9 years STANDARD_DEVIATION 10.7 | 64.8 years STANDARD_DEVIATION 7.4 | 60.8 years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 11 Participants | 2 Participants | 1 Participants | 11 Participants | 2 Participants | 27 Participants |
| Sex: Female, Male Male | 9 Participants | 1 Participants | 6 Participants | 6 Participants | 4 Participants | 26 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 | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 20 | 3 / 3 | 7 / 7 | 17 / 17 | 6 / 6 |
| serious Total, serious adverse events | 9 / 20 | 2 / 3 | 3 / 7 | 4 / 17 | 4 / 6 |
Outcome results
Primary
Investigator Defined Dose Limiting Toxicity (DLT) During First Course of Treatment, Treated Set
Occurence of DLT during the first course of treatment to determine the maximum tolerated dose (MTD) of Afatinib at two different dose schedules in combination with the standard established dose of pemetrexed (500 mg/m2).
Time frame: DLT were assessed during the first cycle (days 1-21)
Population: Treated Set includes all patients that received treatment of Afatinib or Pemetrexed that who were evaluable for MTD determination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Continuous Afatinib 30 mg | Investigator Defined Dose Limiting Toxicity (DLT) During First Course of Treatment, Treated Set | 6 participants |
| Continuous Afatinib 40 mg | Investigator Defined Dose Limiting Toxicity (DLT) During First Course of Treatment, Treated Set | 2 participants |
| Pulsed Afatinib 50 mg | Investigator Defined Dose Limiting Toxicity (DLT) During First Course of Treatment, Treated Set | 1 participants |
| Pulsed Afatinib 60 mg | Investigator Defined Dose Limiting Toxicity (DLT) During First Course of Treatment, Treated Set | 6 participants |
| Pulsed Afatinib 70 mg | Investigator Defined Dose Limiting Toxicity (DLT) During First Course of Treatment, Treated Set | 4 participants |
Secondary
Disease Control
Disease Control is defined as complete response, partial response, or stable disease according to the response evaluation criteria in solid tumours (RECIST) version 1.1.
Time frame: Every 6 weeks before week 48 and every 12 weeks after week 48 until progression
Population: Treated Set includes all patients that received treatment of Afatinib or Pemetrexed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Continuous Afatinib 30 mg | Disease Control | 6 participants |
| Continuous Afatinib 40 mg | Disease Control | 1 participants |
| Pulsed Afatinib 50 mg | Disease Control | 3 participants |
| Pulsed Afatinib 60 mg | Disease Control | 6 participants |
| Pulsed Afatinib 70 mg | Disease Control | 2 participants |
Secondary
Investigator Defined Dose Limiting Toxicity (DLT) During All Courses of Treatment, Treated Set
Occurence of DLT during all courses of treatment with Afatinib at two different dose schedules in combination with the standard established dose of pemetrexed (500 mg/m2).
Time frame: DLT were assessed during all cycles of treatment
Population: Treated Set includes all patients that received treatment of Afatinib or Pemetrexed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Continuous Afatinib 30 mg | Investigator Defined Dose Limiting Toxicity (DLT) During All Courses of Treatment, Treated Set | 11 participants |
| Continuous Afatinib 40 mg | Investigator Defined Dose Limiting Toxicity (DLT) During All Courses of Treatment, Treated Set | 2 participants |
| Pulsed Afatinib 50 mg | Investigator Defined Dose Limiting Toxicity (DLT) During All Courses of Treatment, Treated Set | 3 participants |
| Pulsed Afatinib 60 mg | Investigator Defined Dose Limiting Toxicity (DLT) During All Courses of Treatment, Treated Set | 11 participants |
| Pulsed Afatinib 70 mg | Investigator Defined Dose Limiting Toxicity (DLT) During All Courses of Treatment, Treated Set | 4 participants |
Secondary
Objective Response (OR)
Objective Response is defined as complete response or partial response according to the response evaluation criteria in solid tumours (RECIST) version 1.1. Complete Response (CR): disappearance of all non-target lesions and normalization of tumor marker level; Partial Response (PR): at least 30% decrease of the sum of longest diameter (LD) of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of LD of target lesions together with an absolute increase in the sum of LD of at least 5 millimeters; Stable Disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD.
Time frame: Every 6 weeks before week 48 and every 12 weeks after week 48 until progression
Population: Treated Set includes all patients that received treatment of Afatinib or Pemetrexed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Continuous Afatinib 30 mg | Objective Response (OR) | 2 participants |
| Continuous Afatinib 40 mg | Objective Response (OR) | 0 participants |
| Pulsed Afatinib 50 mg | Objective Response (OR) | 0 participants |
| Pulsed Afatinib 60 mg | Objective Response (OR) | 2 participants |
| Pulsed Afatinib 70 mg | Objective Response (OR) | 0 participants |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from the first treatment to the occurence of tumour progression or death, whichever came first. It was assessed according to RECIST version 1.1 criteria.
Time frame: Every 6 weeks before week 48 and every 12 weeks after week 48 until progression
Population: Treated Set includes all patients that received treatment of Afatinib or Pemetrexed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Continuous Afatinib 30 mg | Progression Free Survival (PFS) | 2.49 months |
| Continuous Afatinib 40 mg | Progression Free Survival (PFS) | 2.52 months |
| Pulsed Afatinib 50 mg | Progression Free Survival (PFS) | 2.56 months |
| Pulsed Afatinib 60 mg | Progression Free Survival (PFS) | 2.52 months |
| Pulsed Afatinib 70 mg | Progression Free Survival (PFS) | 2.69 months |
Secondary
Tumour Shrinkage
Tumour shrinkage is defined as the maximum percentage decrease from baseline in the sum of the longest diameters of target lesions.
Time frame: Every 6 weeks before week 48 and every 12 weeks after week 48 until progression
Population: Treated Set: all patients that received treatment of Afatinib or Pemetrexed and who were evaluated for the longest diameter of the target lesions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Continuous Afatinib 30 mg | Tumour Shrinkage | Patients with any decrease in tumour size | 10 participants |
| Continuous Afatinib 30 mg | Tumour Shrinkage | Patients having >30% decrease in tumour size | 2 participants |
| Continuous Afatinib 40 mg | Tumour Shrinkage | Patients with any decrease in tumour size | 2 participants |
| Continuous Afatinib 40 mg | Tumour Shrinkage | Patients having >30% decrease in tumour size | 0 participants |
| Pulsed Afatinib 50 mg | Tumour Shrinkage | Patients with any decrease in tumour size | 3 participants |
| Pulsed Afatinib 50 mg | Tumour Shrinkage | Patients having >30% decrease in tumour size | 0 participants |
| Pulsed Afatinib 60 mg | Tumour Shrinkage | Patients having >30% decrease in tumour size | 2 participants |
| Pulsed Afatinib 60 mg | Tumour Shrinkage | Patients with any decrease in tumour size | 5 participants |
| Pulsed Afatinib 70 mg | Tumour Shrinkage | Patients with any decrease in tumour size | 1 participants |
| Pulsed Afatinib 70 mg | Tumour Shrinkage | Patients having >30% decrease in tumour size | 0 participants |