A Phase I Dose Escalation Trial of Afatinib Plus Gemcitabine or Plus Docetaxel

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Dose Escalation Trial of Once Daily Oral Treatment Using Afatinib (BIBW2992) Plus Gemcitabine or Docetaxel in Patients With Relapsed or Refractory Solid Tumors.

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Afatinib
* Drug: Afatinib
* Drug: docetaxel
* Drug: gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 1. histologically or cytologically confirmed diagnosis of any advanced or metastatic relapsed or refractory solid tumor. Exclusion criteria: Active brain metastases Patients with known pre-existing interstitial lung disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Afatinib and docetaxel<br> | Drug: Afatinib<br>* Maximum Tolerated Dose of Afatinib in combination with gemcitabine<br>Drug: docetaxel<br>* Maximum Tolerated Dose of Afatinib in combination with docetaxel<br>|
| Afatinib and gemcitabine<br> | Drug: Afatinib<br>* Maximum Tolerated Dose of Afatinib in combination with gemcitabine<br>Drug: gemcitabine<br>* Maximum Tolerated Dose of Afatinib in combination with gemcitabine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) in Process for the Determination of the Maximum Tolerated Dose (MTD). | 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 | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence and Intensity of AEs With Grading According to CTCAE. | 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). | From first drug administration until 28 days after last drug administration, up to 717 days. | 
| Best Overall Response According to RECIST v1.1 Criteria | 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. | From first drug administration until 28 days after last drug administration, up to 717 days. | 
| Disease Control According to RECIST v1.1 | 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. | From first drug administration until 28 days after last drug administration, up to 717 days. | 
| Objective Response According to RECIST v1.1 | 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. | From first drug administration until 28 days after last drug administration, up to 717 days. | 
| Time to Objective Response According to RECIST v1.1 | 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. | 6 weeks, 12 weeks and 24 weeks | 
| Duration of Objective Response According to RECIST v1.1 | Duration of objective response was the time from the first documented complete response or partial response to disease progression or death. | From the first documented complete response or partial response to the time of disease progression or death | 
| Duration of Disease Control According to RECIST v1.1 | Duration of disease control according to RECIST v1.1. | From the first administration of study medication to the time of disease progression or death | 
| Progression Free Survival (PFS) | 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. | From the first administration of study medication to the time of disease progression or death | 
| Overall Survival (OS) | Overall survival was defined as the time from the first administration of study medication to the time of death from any cause. | From the first administration of study medication to the time of death | 
| Area Under the Concentration-time Curve (AUC) Tau,ss of Afatinib | Area under the concentration-time curve of Afatinib in plasma over a uniform dosing interval t at steady state. | 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 | 
| Cmax,ss of Afatinib | Maximum concentration of Afatinib in plasma at steady state. | 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 | 
| AUC 0-tz of Gemcitabine | Area under the concentration-time curve of Gemcitabine in plasma over the time interval from 0 up to the last quantifiable data point | 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 | 
| Cmax of Gemcitabine | Maximum concentration of Gemcitabine in plasma. | 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 | Total Clearance (CL) of Gemcitabine from plasma. | 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 | 
| Volume of Distribution at Steady State (Vss) of Gemcitabine | Apparent 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 | 
| AUC 0-24 of Docetaxel | Area under the concentration-time curve of docetaxel in plasma over the time interval from 0 up to 24 hours | 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 | 
| Cmax of Docetaxel | Maximum concentration of docetaxel in plasma. | 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 | Total Clearance (CL) of Docetaxel from plasma. | 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 | 
| Volume of Distribution at Steady State (Vss) of Docetaxel | Apparent 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 |