BIBW 2992 (Afatinib) in Combination With Pemetrexed in Advanced Solid Tumours

Study Overview
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Brief Summary
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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.

Official Title
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BIBW 2992 Phase I Combination With Pemetrexed in Advanced Solid Tumours

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BIBW 2992 low dose
* Drug: BIBW 2992 high dose
* Drug: pemetrexed
* Drug: pemetrexed
* Drug: BIBW 2992 high dose 6 day
* Drug: pemetrexed
* Drug: pemetrexed
* Drug: pemetrexed
* Drug: pemetrexed
* Drug: BIBW 2992 low dose 6 day
* Drug: BIBW 2992 medium dose 6 day
* Drug: BIBW 2992 medium dose


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 18 or older. Eastern cooperative oncology group performance status of 0-2. Life expectancy of at least 12 weeks. Measurable disease according to Response evaluation criteria in solid tumors 1.1 criteria. Written informed consent Exclusion criteria: Treatment with an investigational drug within the past 28 days prior to the start of therapy Persisting toxicities which are clinically significant from previous therapy Patients who are unwilling or unable to take folic acid and vitamin B12 supplementation Active brain metastases Other active malignancy diagnosed within the past 3 years Concomitant intercurrent illnesses that would limit compliance with trial requirement Patients unable or unwilling to interrupt concomitant administration of Non-steroidal anti-inflammatory drugs (NSAIDS) as per pemetrexed prescribing information Patients who have received prior therapy with BIBW 2992 Left ventricular function by echocardiogram or Multiple gated acquisition scan (MUGA) less than institutional lower limit of normal Absolute neutrophil count (ANC) less than 1,500/mm3 Platelet count less than 100,000/mm3 Hemoglobin less than 90g/L Total bilirubin less than 26µmol/L 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 Serum creatinine level greater than 133µmol/L and/or creatinine clearance (measured or calculated) less than 45 ml/min History or recent gastrointestinal bleeding, obstruction or perforation or malabsorption syndrome and must be able to swallow the BIBW 2992 in whole by mouth. History of interstitial lung disease Women and men who are sexually active and unwilling to use a medically acceptable method of contraception Pregnancy or breast feeding Known or suspected active alcohol or drug abuse Patients unable to comply with the protocol Has a diagnosis of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). Any known hypersensitivity to the trial drugs or their excipients

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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992 low dose<br>patient receives low dose tablet BIBW 2992 po daily plus pemetrexed 500mg/m^2 on day 1 of 21 day cycle | Drug: BIBW 2992 low dose<br>* patient receives low dose BIBW 2992 po daily on day 1 of 21 day cycle<br>Drug: pemetrexed<br>* given intravenously on day 1 of a 21 day cycle<br>|
| Experimental: BIBW 2992 medium dose<br>patient receives medium dose BIBW 2992 po daily plus pemetrexed 500mg/m^2 on day 1 of 21 day cycle | Drug: pemetrexed<br>* given intravenously on day 1 of a 21 day cycle<br>Drug: BIBW 2992 medium dose<br>* patient receives medium dose BIBW 2992 po daily on day 1 of 21 day cycle<br>|
| Experimental: BIBW 2992 high dose<br>patient receives high dose BIBW 2992 po daily plus pemetrexed 500mg/m^2 on day 1 of 21 day cycle | Drug: BIBW 2992 high dose<br>* patient receives high dose BIBW 2992 po daily on day 1 of 21 day cycle<br>Drug: pemetrexed<br>* given intravenously on day 1 of a 21 day cycle<br>|
| Experimental: BIBW 2992 low dose 6 day<br>patient receives low dose BIBW 2992 po daily on days 1-6 plus pemetrexed 500mg/m^2 on day 1 of 21 day cycle | Drug: pemetrexed<br>* given intravenously on day 1 of a 21 day cycle<br>Drug: BIBW 2992 low dose 6 day<br>* patient receives low dose BIBW 2992 po daily on days 1-6 on day 1 of 21 day cycle<br>|
| Experimental: BIBW 2992 medium dose 6 day<br>patient receives medium BIBW 2992 po daily on days 1-6 plus pemetrexed 500mg/m^2 on day 1 of 21 day cycle | Drug: pemetrexed<br>* given intravenously on day 1 of a 21 day cycle<br>Drug: BIBW 2992 medium dose 6 day<br>* patient receives medium dose BIBW 2992 po daily on day1 to 6 of a 21 day cycle<br>|
| Experimental: BIBW 2992 high dose 6 day<br>patient receives high dose BIBW 2992 po daily on days 1-6 plus pemetrexed 500mg/m^2 on day 1 of 21 day cycle | Drug: BIBW 2992 high dose 6 day<br>* patient receives high dose BIBW 2992 po daily on days 1-6 on 1 of 21 day cycle<br>Drug: pemetrexed<br>* given intravenously on day 1 of a 21 day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | DLT were assessed during the first cycle (days 1-21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | DLT were assessed during all cycles of treatment | 
| 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. | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression | 
| 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. | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression | 
| 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. | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression | 
| Tumour Shrinkage | Tumour shrinkage is defined as the maximum percentage decrease from baseline in the sum of the longest diameters of target lesions. | Every 6 weeks before week 48 and every 12 weeks after week 48 until progression |