A Phase I Dose Escalation Trial of Afatinib Plus Gemcitabine or Plus Docetaxel
- Registration Number
- NCT01251653
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
To establish the maximum tolerated dose (MTD) of oral afatinib (BIBW2992) given in combination with gemcitabine or docetaxel in patients with relapsed or refractory tumors.
To assess the safety of the combination. To investigate the PK characteristics of docetaxel or gemcitabine and of oral afatinib (BIBW2992) in the tested treatment schedule. To assess antitumor activity.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 94
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Afatinib and docetaxel Afatinib - Afatinib and docetaxel docetaxel - Afatinib and gemcitabine gemcitabine - Afatinib and gemcitabine Afatinib -
- Primary Outcome Measures
Name Time Method Number of Participants With Dose Limiting Toxicities (DLTs) in Process for the Determination of the Maximum Tolerated Dose (MTD). 3 weeks DLT was based on following criterions: 1. Grade 4 uncomplicated (not associated with fever \>38.5° C (Celsius)) neutropenia for ≥7 days. 2. Grade 3 or 4 neutropenia concomitant with fever \>38.5º C or Grade ≥3 infection. 3. Platelet count of \<25x 10\^9/L or \<50x 10\^9/L with bleeding requiring whole blood transfusion. 4. Grade ≥3 non-haematological toxicity (except untreated nausea, untreated vomiting, or untreated diarrhoea). 5. Grade ≥2 decrease in cardiac left ventricular function. 6. Grade ≥2 worsening of renal function as measured by serum creatinine, newly developed proteinuria, or a newly developed decrease in glomerular filtration rate. Toxicity grading was based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0
- Secondary Outcome Measures
Name Time Method Time to Objective Response According to RECIST v1.1 6 weeks, 12 weeks and 24 weeks Objective response according to RECIST v1.1. Objective response is complete response or partial response for patients with measurable disease. Time to objective response is the time from the start of treatment to the date of first documented complete response or partial response. Descriptive analyses has been performed for the time to objective response (N(%) of patients with first occurrence of objective response at 6, 12 and 24 weeks). Onset of objective response is derived for patient with measurable disease.
AUC 0-tz of Gemcitabine PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 Area under the concentration-time curve of Gemcitabine in plasma over the time interval from 0 up to the last quantifiable data point
The Incidence and Intensity of AEs With Grading According to CTCAE. From first drug administration until 28 days after last drug administration, up to 717 days. The incidence and intensity of adverse events with grading according to CTCAE. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Best Overall Response According to RECIST v1.1 Criteria From first drug administration until 28 days after last drug administration, up to 717 days. Best overall response (according to Response Evaluation Criteria in Solid Tumours \[RECIST\] version 1.1) was the best response recorded at any time from the date of the first administration of afatinib or gemcitabine/docetaxel to the end of treatment (EOT). Partial response is for patients with measurable disease. Missing categories signifies that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.
Duration of Objective Response According to RECIST v1.1 From the first documented complete response or partial response to the time of disease progression or death Duration of objective response was the time from the first documented complete response or partial response to disease progression or death.
Cmax of Gemcitabine PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 Maximum concentration of Gemcitabine in plasma.
Disease Control According to RECIST v1.1 From first drug administration until 28 days after last drug administration, up to 717 days. Disease control according to RECIST v1.1 Disease control is complete response, partial response or stable disease for measurable patients and complete response or non-CR/non-PD for non-measurable patients. Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.
Objective Response According to RECIST v1.1 From first drug administration until 28 days after last drug administration, up to 717 days. Objective response according to RECIST v1.1. Objective response is complete response or partial response for patients with measurable disease. Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.
Cmax,ss of Afatinib PK samples were taken at hours; 167:55, 479:55, 481:05, 482:05, 483:05, 485:05, 487:05 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 Maximum concentration of Afatinib in plasma at steady state.
Duration of Disease Control According to RECIST v1.1 From the first administration of study medication to the time of disease progression or death Duration of disease control according to RECIST v1.1.
Volume of Distribution at Steady State (Vss) of Gemcitabine PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 Apparent volume of distribution at steady state (Vss) of Gemcitabine.
AUC 0-24 of Docetaxel PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 Area under the concentration-time curve of docetaxel in plasma over the time interval from 0 up to 24 hours
Cmax of Docetaxel PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 Maximum concentration of docetaxel in plasma.
Volume of Distribution at Steady State (Vss) of Docetaxel PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 Apparent volume of distribution at steady state (Vss) of Docetaxel.
Progression Free Survival (PFS) From the first administration of study medication to the time of disease progression or death Progression-free survival was defined as the time from the first administration of study medication to the time of disease progression or death, whichever occurred first.
Overall Survival (OS) From the first administration of study medication to the time of death Overall survival was defined as the time from the first administration of study medication to the time of death from any cause.
Area Under the Concentration-time Curve (AUC) Tau,ss of Afatinib PK samples were taken at hours; 167:55, 479:55, 481:05, 482:05, 483:05, 485:05, 487:05 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 Area under the concentration-time curve of Afatinib in plasma over a uniform dosing interval t at steady state.
Total Clearance (CL) of Gemcitabine PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 Total Clearance (CL) of Gemcitabine from plasma.
Total Clearance (CL) of Docetaxel PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 Total Clearance (CL) of Docetaxel from plasma.
Trial Locations
- Locations (3)
1200.93.33002 Boehringer Ingelheim Investigational Site
🇫🇷Dijon, France
1200.93.33001 Boehringer Ingelheim Investigational Site
🇫🇷Saint-Herblain cedex, France
1200.93.33003 Boehringer Ingelheim Investigational Site
🇫🇷Toulouse, France