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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00875433
First received: April 2, 2009
Last updated: December 5, 2013
Last verified: October 2013
  Purpose

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).


Condition Intervention Phase
Neoplasms
Drug: BIBW 2992
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Objective Response (OR) [ Time Frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. ] [ Designated as safety issue: No ]
    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).

  • Average Time-matched QT Corrected by the Fridericia Formula (QTcF) Change From Baseline to Day 14 [ Time Frame: 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. ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Progression-free Survival (PFS) [ Time Frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. ] [ Designated as safety issue: No ]
    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.

  • Overall Survival (OS) [ Time Frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. ] [ Designated as safety issue: No ]
    Overall survival (OS) is defined as time from start of treatment to death.

  • Disease Control [ Time Frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. ] [ Designated as safety issue: No ]
    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).

  • Duration of Disease Control (DC) [ Time Frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. ] [ Designated as safety issue: No ]
    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).

  • Patients With Notable Findings in QTcF on Day 14 [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
    Notable findings are defined as a QTcF>500 ms or an increase in QTcF of >60ms.

  • Patients With Clinically Relevant Findings in ECG on Day 14 [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
    Patients with clinically relevant findings in Electrocardiogram data (ECG) on day 14.

  • Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point [ Time Frame: Baseline and day 14 (at 1, 2, 3, 4, 5, 6, 7, 10, 24 hours post-dose ) ] [ Designated as safety issue: No ]
    Individual QTcF measurements at each time-point. Response was defined as the change from baseline. Analysis adjusted for baseline using a mixed model.

  • Average Time-matched QT Change From Baseline to Day 14 [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Average time-matched QT change from baseline to day 14 over 1 to 24 hours following administration of afatinib.

  • Patients With Notable Findings in QT on Day 14 [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
    Number of Patients with notable findings in QT on day 14. Notable findings are defined as a QT>500 ms.

  • Average Time-matched Heart Rate Change From Baseline to Day 14. [ Time Frame: The day before the first drug dose (baseline) and the day 14. ] [ Designated as safety issue: No ]
    Average time-matched heart rate change from baseline to day 14.

  • Highest CTC Grade for Adverse Events [ Time Frame: First administration of trial medication until 28 days after last administration of trial medication ] [ Designated as safety issue: No ]
    Highest Common Terminology Criteria (CTC) grade for adverse events

  • Area Under Curve 0-24 Hours (AUC0-24) on Day 1 [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 ] [ Designated as safety issue: No ]
    AUC0-24 represents the area under the concentration curve of afatinib in plasma from 0 to 24 hours on Day 1.

  • Maximum Concentration (Cmax) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 ] [ Designated as safety issue: No ]
    Cmax represents the maximum measured concentration of afatinib in plasma on Day 1.

  • Time From Dosing to the Maximum Concentration (Tmax) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 ] [ Designated as safety issue: No ]
    tmax represents the time from dosing to the maximum concentration of afatinib in plasma on Day 1.

  • Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 ] [ Designated as safety issue: No ]
    AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau (24h) at steady state (Day14).

  • Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 ] [ Designated as safety issue: No ]
    Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state (Day 14).

  • Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 ] [ Designated as safety issue: No ]
    tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state (Day 14).

  • Accumulation Ratio of AUC Values (R_A,AUC) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14 ] [ Designated as safety issue: No ]
    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

  • Accumulation Ratio of AUC Values (R_A,Cmax) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14 ] [ Designated as safety issue: No ]
    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

  • Percentage Peak Trough Fluctuation (PTF) [ Time Frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 ] [ Designated as safety issue: No ]
    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.


Enrollment: 60
Study Start Date: March 2009
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Monotherapy
BIBW 2992 high dose, once daily, continuous, monotherapy
Drug: BIBW 2992
patients to receive continuous oral daily dosing of BIBW 2992

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Male or female patients aged at least 18 years old.
  2. 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).
  3. 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.
  4. Life expectancy of at least 3 months.
  5. Written informed consent that is consistent with ICH-GCP guidelines.
  6. Eastern Cooperative Oncology Group (ECOG) performance score 0,1 or 2.
  7. Patients must have recovered from any previous surgery.
  8. 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:

  1. 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.
  2. 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;

  1. 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).
  2. 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.
  3. Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure.
  4. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas).
  5. Less than four weeks from prior treatment with bevacizumab.
  6. Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00875433

Locations
United Kingdom
1200.24.4403 Boehringer Ingelheim Investigational Site
Guildford, United Kingdom
1200.24.4404 Boehringer Ingelheim Investigational Site
London, United Kingdom
1200.24.4402 Boehringer Ingelheim Investigational Site
London, United Kingdom
1200.24.4401 Boehringer Ingelheim Investigational Site
Sutton, United Kingdom
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00875433     History of Changes
Other Study ID Numbers: 1200.24, 2008-006288-36
Study First Received: April 2, 2009
Results First Received: August 8, 2013
Last Updated: December 5, 2013
Health Authority: Great Britain: MHRA
United States: Food and Drug Administration

ClinicalTrials.gov processed this record on September 22, 2014