Neoplasms
Conditions
Brief summary
Study to determine the maximum tolerated dose of BIBW 2992 when combined with backbone chemotherapies consisting in cisplatin plus paclitaxel or cisplatin plus 5 FU. The overall safety, the pharmacokinetics and the anti-tumour efficacy will also be assessed.
Interventions
DRUGBIBW 2992
In each arm, BIBW 2992 dose will be escalated to determine MTD. Starting dose will be 20mg daily followed by 40 mg (with the option of an intermediary dose of 30 mg) then 50mg daily. Dose escalation will stop at 50 mg. No intra patient dose escalation.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with histologically or cytologically confirmed diagnosis of non resectable and / or metastatic cancer, preferably squamous cell carcinomas of head and neck, oesophagus, lung or cervix 2. Indication for a standard treatment with either cisplatin plus paclitaxel or cisplatin plus 5 FU as judged by the investigator 3. Age 18 years or older. 4. Life expectancy of at least three (3) months. 5. Written informed consent that is consistent with ICH-GCP guidelines. 6. Eastern Cooperative Oncology Group (ECOG) performance score less or equal 2. 7. Patients must have recovered from any therapy-related toxicity from previous chemo-, hormone-, immuno-, or radiotherapies. 8. Patients recovered from previous surgery.
Exclusion criteria
1. Active infectious disease. 2. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhoea. 3. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol. 4. Patients with untreated or symptomatic brain metastases. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least four (4) weeks, no history of cerebral oedema or bleeding in the past four (4) weeks and no requirement for steroids or anti-epileptic therapy. 5. Cardiac left ventricular function with resting ejection fraction less than 50% 6. Absolute neutrophil count (ANC) less than 1500 / mm3. 7. Platelets count less than 100 000/mm3. 8. Bilirubin more than 1.5 x upper limit of institutional norm. 9. Aspartate amino transferase (AST) or alanine amino transferase (ALT) more than 3 x upper limit of institutional norm. 10. Serum creatinine more than 1.5 x upper limit of institutional norm. 11. Women and men sexually active and unwilling to use a medically acceptable method of contraception. 12. Pregnancy or breast-feeding. 13. Treatment with other investigational drugs; chemotherapy, immunotherapy, or radiotherapy or participation in another clinical study with anti-cancer therapy within the past 4 weeks before start of therapy or concomitantly with this study. 14. Treatment with an EGFR- or HER2 inhibiting drug within the past four weeks before start of therapy or concomitantly with this study (2 weeks for trastuzumab). 15. Patients unable to comply with the protocol. 16. Active alcohol or drug abuse.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 21 days | Number of participants with DLT in the first cycle (21 days) for the determination of the MTD. |
| Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | 21 days | The MTD was determined using a standard 3 +3 dose escalation cohort design. The sample size and the number of patients who receive each dose in this design depends on the frequency of DLT at each dose level in cycle 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Objective Response | Tumor assessment were performed at screening and every 2nd cycle until end of follow up (=end of treatment + 30 days +/- 7 days) | Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.0. Objective response is defined as complete response (CR) and partial response (PR). |
| Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 0.05hours (h) before administration and 1h, 2h, 2h 55 minutes (min), 4h, 4h 30min, 5h, 6h, 8h, 10h, 24h, 48h, 216h, 480h after administration | Cmax,ss represents the maximum concentration of afatinib in plasma at steady state |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pac175 + Cis50 + Afatinib20 Patients received continous daily dosing with Afatinib 20mg film-coated tablets over 21 day treatment cycles and infusions of Paclitaxel 175mg/m\^2 and Cisplatin 50mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 3 |
| Pac175 + Cis75 + Afatinib20 Patients received continous daily dosing with Afatinib 20mg film-coated tablets over 21 day treatment cycles and infusions of Paclitaxel 175mg/m\^2 and Cisplatin 75mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 6 |
| Pac175 + Cis75 + Afatinib30 Patients received continous daily dosing with Afatinib 30mg film-coated tablets over 21 day treatment cycles and infusions of Paclitaxel 175mg/m\^2 and Cisplatin 75mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 5 |
| Pac175 + Cis75 + Afatinib40 Patients received continous daily dosing with Afatinib 40mg film-coated tablets over 21 day treatment cycles and infusions of Paclitaxel 175mg/m\^2 and Cisplatin 75mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 11 |
| Pac175 + Cis75 + Afatinib50 Patients received continous daily dosing with Afatinib 50mg film-coated tablets over 21 day treatment cycles and infusions of Paclitaxel 175mg/m\^2 and Cisplatin 75mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 1 |
| Cis75 + 5FU750 + Afatinib20 Patients received continous daily dosing with Afatinib 20mg film-coated tablets over 21 day treatment cycles and infusions of 5-Fluorouracil 750mg/m\^2 and Cisplatin 75mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 3 |
| Cis75 + 5FU750 + Afatinib30 Patients received continous daily dosing with Afatinib 30mg film-coated tablets over 21 day treatment cycles and infusions of 5-Fluorouracil 750mg/m\^2 and Cisplatin 75mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 7 |
| Cis75 + 5FU750 + Afatinib40 Patients received continous daily dosing with Afatinib 40mg film-coated tablets over 21 day treatment cycles and infusions of 5-Fluorouracil 750mg/m\^2 and Cisplatin 75mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 3 |
| Cis100 + 5FU750 + Afatinib30 Patients received continous daily dosing with Afatinib 30mg film-coated tablets over 21 day treatment cycles and infusions of 5-Fluorouracil 750mg/m\^2 and Cisplatin 100mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 5 |
| Cis100 + 5FU1000 + Afatinib30 Patients received continous daily dosing with Afatinib 30mg film-coated tablets over 21 day treatment cycles and infusions of 5-Fluorouracil 1000mg/m\^2 and Cisplatin 100mg/m\^2 on day 1 of each cycle. Treatment until disease progression or toxicity. | 3 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 1 | 0 | 0 | 3 | 1 | 0 | 3 |
| Overall Study | Dose limiting toxicity (DLT) | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | On patient request due to toxicities | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Progressive disease | 3 | 5 | 3 | 8 | 0 | 3 | 3 | 1 | 5 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Pac175 + Cis50 + Afatinib20 | Pac175 + Cis75 + Afatinib20 | Pac175 + Cis75 + Afatinib30 | Pac175 + Cis75 + Afatinib40 | Pac175 + Cis75 + Afatinib50 | Cis75 + 5FU750 + Afatinib20 | Cis75 + 5FU750 + Afatinib30 | Cis75 + 5FU750 + Afatinib40 | Cis100 + 5FU750 + Afatinib30 | Cis100 + 5FU1000 + Afatinib30 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.7 years STANDARD_DEVIATION 14 | 61.8 years STANDARD_DEVIATION 15.6 | 61.8 years STANDARD_DEVIATION 5.9 | 58.1 years STANDARD_DEVIATION 7.8 | 54.0 years | 52.7 years STANDARD_DEVIATION 9.7 | 53.1 years STANDARD_DEVIATION 16.1 | 65.0 years STANDARD_DEVIATION 8.5 | 59.2 years STANDARD_DEVIATION 14.4 | 63.7 years STANDARD_DEVIATION 9.3 | 58.58 years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 19 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 3 Participants | 8 Participants | 1 Participants | 3 Participants | 5 Participants | 1 Participants | 2 Participants | 2 Participants | 28 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 5 / 5 | 11 / 11 | 1 / 1 | 3 / 3 | 7 / 7 | 3 / 3 | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 5 / 6 | 4 / 5 | 7 / 11 | 1 / 1 | 2 / 3 | 6 / 7 | 3 / 3 | 1 / 5 | 3 / 3 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) for Regimen A and Regimen B
The MTD was determined using a standard 3 +3 dose escalation cohort design. The sample size and the number of patients who receive each dose in this design depends on the frequency of DLT at each dose level in cycle 1.
Time frame: 21 days
Population: Treated Set (TS) - TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pac175 + Cis50 + Afatinib20 | Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | Maximum tolerated dose - Cisplatin | 75 mg/m^2 |
| Pac175 + Cis50 + Afatinib20 | Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | Maximum tolerated dose - Pac (A) or 5-FU (B) | 175 mg/m^2 |
| Pac175 + Cis50 + Afatinib20 | Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | Maximum tolerated dose - Afatinib | 20 mg/m^2 |
| Pac175 + Cis75 + Afatinib20 | Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | Maximum tolerated dose - Cisplatin | 100 mg/m^2 |
| Pac175 + Cis75 + Afatinib20 | Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | Maximum tolerated dose - Pac (A) or 5-FU (B) | 750 mg/m^2 |
| Pac175 + Cis75 + Afatinib20 | Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | Maximum tolerated dose - Afatinib | 30 mg/m^2 |
Primary
Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
Number of participants with DLT in the first cycle (21 days) for the determination of the MTD.
Time frame: 21 days
Population: Treated Set (TS) - TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pac175 + Cis50 + Afatinib20 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Pac175 + Cis75 + Afatinib20 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Pac175 + Cis75 + Afatinib30 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 Participants |
| Pac175 + Cis75 + Afatinib40 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 Participants |
| Pac175 + Cis75 + Afatinib50 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 1 Participants |
| Cis75 + 5FU750 + Afatinib20 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Cis75 + 5FU750 + Afatinib30 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Cis75 + 5FU750 + Afatinib40 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 Participants |
| Cis100 + 5FU750 + Afatinib30 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Cis100 + 5FU1000 + Afatinib30 | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 Participants |
Secondary
Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss)
Cmax,ss represents the maximum concentration of afatinib in plasma at steady state
Time frame: 0.05hours (h) before administration and 1h, 2h, 2h 55 minutes (min), 4h, 4h 30min, 5h, 6h, 8h, 10h, 24h, 48h, 216h, 480h after administration
Population: The pharmacokinetic analysis set includes all patients who took at least one dose of trial medication and provided at least one blood sample following drug administration. Values were excluded from descriptive statistics when a comparison with plasma concentrations in the same treatment group was impossible.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pac175 + Cis50 + Afatinib20 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 22.1 ng/mL | Geometric Coefficient of Variation 22.5 |
| Pac175 + Cis75 + Afatinib20 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 18.0 ng/mL | Geometric Coefficient of Variation 24.9 |
| Pac175 + Cis75 + Afatinib30 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 17.7 ng/mL | Geometric Coefficient of Variation 13.2 |
| Pac175 + Cis75 + Afatinib40 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 32.1 ng/mL | Geometric Coefficient of Variation 79.2 |
| Cis75 + 5FU750 + Afatinib20 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 48.9 ng/mL | Geometric Coefficient of Variation 26 |
| Cis75 + 5FU750 + Afatinib30 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 57.0 ng/mL | Geometric Coefficient of Variation 41.1 |
| Cis75 + 5FU750 + Afatinib40 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 32.7 ng/mL | — |
| Cis100 + 5FU750 + Afatinib30 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 13.4 ng/mL | Geometric Coefficient of Variation 28.9 |
| Cis100 + 5FU1000 + Afatinib30 | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 17.3 ng/mL | — |
Secondary
Number of Patients With Objective Response
Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.0. Objective response is defined as complete response (CR) and partial response (PR).
Time frame: Tumor assessment were performed at screening and every 2nd cycle until end of follow up (=end of treatment + 30 days +/- 7 days)
Population: Treated Set (TS) - TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pac175 + Cis50 + Afatinib20 | Number of Patients With Objective Response | 1 Participants |
| Pac175 + Cis75 + Afatinib20 | Number of Patients With Objective Response | 0 Participants |
| Pac175 + Cis75 + Afatinib30 | Number of Patients With Objective Response | 0 Participants |
| Pac175 + Cis75 + Afatinib40 | Number of Patients With Objective Response | 4 Participants |
| Pac175 + Cis75 + Afatinib50 | Number of Patients With Objective Response | 0 Participants |
| Cis75 + 5FU750 + Afatinib20 | Number of Patients With Objective Response | 1 Participants |
| Cis75 + 5FU750 + Afatinib30 | Number of Patients With Objective Response | 0 Participants |
| Cis75 + 5FU750 + Afatinib40 | Number of Patients With Objective Response | 0 Participants |
| Cis100 + 5FU750 + Afatinib30 | Number of Patients With Objective Response | 0 Participants |
| Cis100 + 5FU1000 + Afatinib30 | Number of Patients With Objective Response | 0 Participants |