Afatinib (BIBW 2992) QTcF Trial in Patients With Relapsed or Refractory Solid Tumours

Study Overview
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Brief Summary
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A phase II trial to assess the impact of afatinib (BIBW 2992) on the heart (QTcF) and the effectiveness of afatinib (BIBW 2992) in treating certain cancers. Cancers studied will include glioblastoma and cancers which have spread to the brain (metastases).

Official Title
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Phase II Open Label Trial to Assess the Efficacy and the Impact on QTcF of Continuous Oral BIBW 2992 at a Daily Dose of 50mg in Patients With Relapsed or Refractory Solid Tumours Including Patients With Brain Metastases and Those With Glioblastoma Not Amenable to Other Therapy

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BIBW 2992


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients aged at least 18 years old. Histologically or cytologically confirmed diagnosis of a solid malignant tumour, known to express EGFR/HER2 that is either refractory to standard therapies, or for which no standard treatment is available (including patients with brain metastases). At least one tumor lesion that can accurately be measured by computed tomography (CT) or magnetic resonance imaging (MRI) in at least one dimension with longest diameter to be recorded as greater than or equal to 20 mm using conventional techniques or greater than or equal to 10 mm with spiral CT scan. Life expectancy of at least 3 months. Written informed consent that is consistent with ICH-GCP guidelines. Eastern Cooperative Oncology Group (ECOG) performance score 0,1 or 2. Patients must have recovered from any previous surgery. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment. Breast feeding mothers will be excluded since these agents may be toxic to infants. For patients with Glioma and brain metastases the following additional inclusion criteria should apply: Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemo-radiotherapy. Patients with prior low-grade glioma are eligible if histological assessment demonstrates transformation to WHO Grade IV malignant glioma. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on Gd MRI performed within 14 days prior to first treatment (Day 1). Exclusion criteria: Major exclusion criteria; 9. Radiotherapy within the past 2 weeks prior to treatment with the trial drug. 10. Chemo-, hormone- (other than megestrol acetate or steroids required for maintenance non-cancer therapy) or immunotherapy within the past 4 weeks before first drug administration. 11. Patients not completely recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapies to CTC < Grade 1. Prior chemotherapy is allowed if completed at least 4 weeks prior to first trial treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from the acute toxicities of that therapy. 12. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2 inhibiting drugs within the past four weeks before start of therapy or concomitantly with this trial. 15. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, including New York Heart Association (NYHA) functional classification of 3. 16. Cardiac left ventricular function with resting ejection fraction < 50% measured by multigated blood pool imaging of the heart (MUGA scan) or Echocardiogram. 17. QTcF- interval > 470 ms at screening. 18. PR-interval > 230 ms at screening. 19. QRS-interval >120 ms at screening. 20. ST-segment and T/U-wave abnormalities at screening, as will be assessed by a cardiology specialist of a central lab. 21. Absolute neutrophil count (ANC) < 1,500/mm3. 22. Platelet count < 100,000 / mm3. 23. Bilirubin > 1.5 mg / dl (>26 micro mol / L, SI unit equivalent). Aspartate amino transferase (AST) or alanine amino transferase (ALT) > or equal to three times the upper limit of normal (if related to liver metastases > five times the upper limit of normal). 24. Serum creatinine > 1.5 times of the upper normal limit or calculated/measured creatinine clearance > or equal to 45 ml / min. 25. Patients with known Interstitial Lung Disease (ILD) For Patients with glioma and brain metastases additional exclusion criteria apply; 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. Steroids will be allowed. Anti-epileptic therapy will be allowed if no changes are anticipated within the initial 14 days of treatment (QTC-evaluation). Less than 4 weeks between radiotherapy and start of study treatment, unless new enhancing lesion outside of radiation field or radiologically progressive on two consecutive MRI scans at least four weeks apart or biopsy-proven recurrence. Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas). Less than four weeks from prior treatment with bevacizumab. Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study.

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: Monotherapy<br>BIBW 2992 high dose, once daily, continuous, monotherapy | Drug: BIBW 2992<br>* patients to receive continuous oral daily dosing of BIBW 2992<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) | OR is defined as complete response and partial response (PR) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST) for solid tumours (excluding glioblastomas). | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Average Time-matched QT Corrected by the Fridericia Formula (QTcF) Change From Baseline to Day 14 | Average time-matched QT corrected by the Fridericia formula (QTcF) change from baseline to day 14 over 1 to 24 hours following administration of afatinib. | The day before the first drug dose (baseline) and the day 14. Electrocardiograms (ECG) were performed at time point 0 and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h, 24 h thereafter. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. It was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas) as well as by the investigators assessment. Median time results from unstratified Kaplan-Meier estimates. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Overall Survival (OS) | Overall survival (OS) is defined as time from start of treatment to death. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Disease Control | Disease control was defined as CR, PR or stable disease (SD) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas). | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Duration of Disease Control (DC) | Duration of Disease control (DC). DC was defined as CR, PR or stable disease (SD) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas). | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Patients With Notable Findings in QTcF on Day 14 | Notable findings are defined as a QTcF>500 ms or an increase in QTcF of >60ms. | Day 14 | 
| Patients With Clinically Relevant Findings in ECG on Day 14 | Patients with clinically relevant findings in Electrocardiogram data (ECG) on day 14. | Day 14 | 
| Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Individual QTcF measurements at each time-point. Response was defined as the change from baseline. Analysis adjusted for baseline using a mixed model. | Baseline and day 14 (at 1, 2, 3, 4, 5, 6, 7, 10, 24 hours post-dose ) | 
| Average Time-matched QT Change From Baseline to Day 14 | Average time-matched QT change from baseline to day 14 over 1 to 24 hours following administration of afatinib. | The day before the first drug dose (baseline) and the day 14. Electrocardiograms (ECG) were performed at time point 0 and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h, 24 h thereafter. | 
| Patients With Notable Findings in QT on Day 14 | Number of Patients with notable findings in QT on day 14. Notable findings are defined as a QT>500 ms. | Day 14 | 
| Average Time-matched Heart Rate Change From Baseline to Day 14. | Average time-matched heart rate change from baseline to day 14. | The day before the first drug dose (baseline) and the day 14. | 
| Highest CTC Grade for Adverse Events | Highest Common Terminology Criteria (CTC) grade for adverse events | First administration of trial medication until 28 days after last administration of trial medication | 
| Area Under Curve 0-24 Hours (AUC0-24) on Day 1 | AUC0-24 represents the area under the concentration curve of afatinib in plasma from 0 to 24 hours on Day 1. | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 | 
| Maximum Concentration (Cmax) | Cmax represents the maximum measured concentration of afatinib in plasma on Day 1. | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 | 
| Time From Dosing to the Maximum Concentration (Tmax) | tmax represents the time from dosing to the maximum concentration of afatinib in plasma on Day 1. | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 | 
| Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau (24h) at steady state (Day14). | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 | 
| Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state (Day 14). | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 | 
| Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state (Day 14). | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 | 
| Accumulation Ratio of AUC Values (R_A,AUC) | R_A,AUC represents the accumulation ratio of AUC values after multiple dose administration over a uniform dosing interval t between days 1 and 14 | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14 | 
| Accumulation Ratio of AUC Values (R_A,Cmax) | R_A,Cmax represents the accumulation ratio of Cmax values after multiple dose administration over a uniform dosing interval t between days 1 and 14 | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14 | 
| Percentage Peak Trough Fluctuation (PTF) | PTF represents the percentage peak trough fluctuation. PTF is defined as difference between maximum and minimum concentration at steady state divided by the average concentration multiplied with 100 to report as percentage. | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 |