Phase II Trial of BIBW 2992 (Afatinib) in Genetically Pre-screened Cancers With EGFR and/or HER2 Gene Amplification.

This is a Phase II open-label exploratory trial of BIBW 2992 administered to patients with tumors of various histologies found to possess EGFR and/or HER2 gene amplification, or EGFR activating mutations.


Eligibility Criteria:
Inclusion criteria:

There are 2 Steps in the screening process:

Step 1 Inclusion criteria for pre-screening:

1. Histologically confirmed diagnosis of advanced cancer of one of the following four tumor type categories:

   Category 1, Gastric, GE junction, or Esophageal cancer Category 2, Biliary or gallbladder cancer Category 3, TCC urothelial tract, and Category 4, Gynecological cancers
2. Measurable disease by RECIST criteria.
3. Willingness and ability to give written informed consents consistent with ICHGCP guidelines.
4. Life expectancy of at least three (3) months.
5. Eastern Cooperative Oncology Group performance score 0, 1 or 2.
6. Age \>18 years.

Step 2 Inclusion criteria for enrollment:

Patients who have tested positive for FISH and are considered candidate for this trial must meet all of the following inclusion criteria:

1. Histologically confirmed diagnosis of advanced cancer of one of the following four tumor type categories:

   Category 1, Gastric, GE junction, or Esophageal cancer Category 2, Biliary or gallbladder cancer Category 3, TCC urothelial tract, and Category 4, Gynecological cancers
2. Documented failure to respond or progression of underlying cancer after at least one line of prior chemotherapy.
3. EGFR and/or HER2 gene amplification by FISH testing or patients with tumors that harbor known activating EGFR mutations.
4. Measurable disease by RECIST criteria.
5. Willingness and ability to give written informed consents consistent with ICH-GCP guidelines.
6. Life expectancy of at least three (3) months.
7. Eastern Cooperative Oncology Group performance score 0, 1 or 2.
8. Age \>18 years.

Exclusion criteria:

1. Prior treatment with gefitinib, erlotinib, lapatinib and/or other EGFR TKIs.
2. Treatment with cytotoxic anti-cancer-therapies or investigational drugs during the last four weeks prior to the first treatment with the trial drug. (a shorter duration may be considered for patients treated with oral, non cytotoxic drugs on an individual basis and upon discussion between the principal investigator and sponsor)
3. Inability to take BIBW 2992 by mouth (BIBW 2992 may not be crushed or administered via Gastrostomy-tube)
4. Chronic diarrhea or other gastrointestinal disorders that may interfere with the absorption of the trial drug.
5. History of other malignancies unless free of disease for at least 3 years (except for appropriately treated superficial non-melanoma skin cancer and surgically cured cervical cancer in situ).
6. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomization.
7. Resting left ventricular ejection fraction \<50% OR below the institution's lower limit of normal (if the institutions lower limit is above 50%), measured by MUGA scan or echocardiogram.
8. Active infectious disease
9. Serious illness, concomitant non-oncological disease or mental problems considered by the investigator to be incompatible with participation in this trial.
10. Active/symptomatic brain metastases. Patients with a history of treated brain metastases must have stable or normal brain MRI scan at screening and be at least three months post-radiation or surgery for brain metastasis.
11. Absolute Neutrophil Count (ANC) less than 1,000/mm3.
12. Platelet count less than 100,000/mm3.
13. Hemoglobin Level less than 9.0 grams/dl.
14. Total Bilirubin greater than 1.5 mg/dl; higher Total Bilirubin values may be acceptable for patients with known Gilbert¿s disease, approval by the PI and sponsor will be necessary.
15. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 times the upper limit of normal; or 5 times the upper limit of normal in patients with neoplastic liver involvement.
16. Serum creatinine greater than 1.5 x upper limit of normal for the institution.
17. Patients who are sexually active and unwilling to use simultaneously two medically acceptable method of contraception, one of which being a barrier type method such as condom.
18. Pregnancy or breast-feeding.
19. Patients unable to comply with the protocol
20. Active alcohol and/or substance abuse.
21. Continuation of therapy-related toxicities from prior anti cancer therapies, prior surgery, of CTCAE Grade \>=2 at the time of the first administration of the trial drug.
22. Patients with known pre-existing interstitial lung disease.
23. Requirement for treatment with any of the prohibited concomitant medications: additional experimental anti-cancer treatment and/or standard chemotherapy, immunotherapy, hormone treatment or radiotherapy; P-gp inhibitors