A Phase I Open Label Trial of Continuous Dosing With BIBW 2992 Combined With Paclitaxel and BIBW 2992 Combined With Paclitaxel and Bevacizumab, BIBW 2992 Combined With Carboplatin and BIBW 2992 Combined With Paclitaxel and Carboplatin in Patients With Advanced Solid Tumours
1. Male or female patients (patients) with a histologically confirmed diagnosis of
malignancy that is now advanced, non-resectable and / or metastatic.
2. Age 18 years old or older.
3. Life expectancy of at least 3 months.
4. Written informed consent that is consistent with ICH-GCP guidelines.
5. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.
6. Patients must have recovered from any previous surgery.
7. Adequate organ function including the following:
8. Cardiac left ventricular function with resting ejection fraction greater than or
equal to 50%
9. Absolute neutrophil count of greater than or equal to 1,500/microlitres; greater than
2000/microlitres for carboplatin
10. Platelets greater than or equal to 100,000/microlitres
11. Total bilirubin less than or equal to 1.5 mg/dl (<26 micromol /L, SI unit
12. AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal.
13. Creatinine less than or equal to 1.5 mg/dl (less than or equal to 132 micromol per
liter, SI unit equivalent).
14. 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.
1. Active infectious disease
2. Serious illness or concomitant non-oncological disease considered by the investigator
to be incompatible with the protocol
3. GI tract disease resulting in an inability to take oral medication or a requirement
for IV alimentation, prior surgical procedures affecting absorption, or active peptic
4. Significant cardiovascular disease (a history of congestive heart failure requiring
therapy, a need for anti-arrhythmic therapy for a ventricular arrhythmia, unstable
angina pectoris or myocardial infarction within 6 months prior to trial entry).
5. Patients who require full-dose anticoagulation.
6. Patients not completely recovered from any therapy-related toxicities from previous
chemo-, hormone-, immuno-, or radiotherapies to CTC less than or equal to Grade 1.
Prior chemotherapy is allowed if completed at least 4 weeks prior to 1st trial
treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered
from the acute toxicities of that therapy.
7. 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 8 weeks, no history of cerebral oedema or bleeding in the
past 8 weeks and no requirement for steroids or anti-epileptic therapy
8. Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause.
9. Patients on immunosuppressant therapy or with known HIV infection.
10. Treatment with any of the following within 4 weeks of starting trial medication, or
during the trial, is not permitted: chemo-, immuno-, radio- (small field palliative
radiotherapy is allowed provided this does not represent clear disease progression),
biological therapies (including trastuzumab), hormone therapy (excluding LHRH
agonists in prostate cancer, or bisphosphonates), or treatment with other
11. Participation in another clinical trial within the past 4 weeks before start of
therapy or concomitantly with this trial.
12. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2
inhibiting drugs within the past 4 weeks before start of therapy or concomitantly
with this trial.
13. Patients with known or suspected hypersensitivity to any of the trial drugs, their
excipients or similar compounds.
14. Patients unable to comply with the protocol.
15. Active alcohol or drug abuse.
16. Patients with known pre-existing interstitial lung disease
Additional exclusion criteria for patients recruited to cohorts B:
17. Patients with known or suspected hypersensitivity to bevacizumab, its excipients or
Chinese hamster ovary cell products or other recombinant human or humanised
18. Patients with brain metastases (a brain scan is not required unless the patient shows
signs and symptoms of brain metastases and a brain scan is performed to rule out the
presence of brain metastases).
19. Patients with intra-abdominal inflammation .
20. Major surgery within 4 weeks of starting treatment or any wound(s) deemed by the
investigator to pose a significant risk to the patient in the event of delayed
21. Prior treatment with anthracycline and/or prior radiation to the chest wall (
patients in these categories will only be entered into the study where the
investigator deems the benefit to the patient to outweigh the risk).
22. Patients with any of the following conditions: significant hypertension, significant
haemoptysis, known brian metastases, thrombotic or haemorrhagic disorders, INR
greater than or equal to 1.5 abnormal PTT, therapeutic anti-coagulation, squamous
non small cell lung cancer Additional exclusion criteria for patients recruited to
cohorts C and D
- Patients with severe myelosuppression; i.e. absolute neutrophil count less than
- Patients with renal impairment (creatinine clearance less than 60ml per minute
by Cockcroft-Gault equation)