Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 (Afatinib) Plus Sirolimus (Rapamune®) in Patients With Non-small Cell Lung Cancer Harbouring an EGFR Mutation and/or Disease Progression Following Prior Erlotinib or Gefitinib

• The primary endpoint is the safety of BIBW 2992 given in combination with Sirolimus assessed based on: [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• 1) dose limiting toxicities (DLT) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• 2) adverse events according to CTCAE, version 3.0 [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

• 1)Drug concentration monitoring of BIBW 2992 and Sirolimus during the first cycle of therapy [ Time Frame: Multiple time points during the trial ] [ Designated as safety issue: No ]
• 2)Objective response [ Time Frame: Multiple time points during the trial ] [ Designated as safety issue: No ]
• 3)Disease Control [ Time Frame: Multiple time points during the trial ] [ Designated as safety issue: No ]
• 4) Exploratory examination of EGFR mutations (Exons 19, 20 and 21) in serum/plasma DNA and tumour DNA. [ Time Frame: Multiple time points during the trial ] [ Designated as safety issue: No ]
• 5) Exploratory examination of expression of other additional biomarkers. [ Time Frame: Multiple time points during the trial ] [ Designated as safety issue: No ]

The primary objective of this trial is to identify the Maximum Tolerated Dose of BIBW 2992 therapy when given continuously in combination with Sirolimus.

The MTD will be based on the Dose Limiting Toxicity information collected during the first two cycles.

Overall safety, pharmacokinetics and anti-tumour efficacy will be evaluated as secondary objectives.

• Drug: BIBW 2992
  Dose escalation (19-40 patients): low or high dose oral + 12 addit. pat. at MTD, until progression or undue AEs
• Drug: Sirolimus (rapamycin)
  Dose escalation (19-40 patients): several dose levels + 12 addit. pat. at MTD until progression or undue AEs.

Inclusion criteria:

1. Pathologically or cytologically confirmed diagnosis of Stage IIIB or Stage IV NSCLC
2. Patients who have failed conventional treatment (at least 1 prior treatment line), or for whom no therapy of proven efficacy exists

3. Patients whose tumors:

   • are EGFR mutation-positive or
   • are EGFR mutation-negative or unknown provided they had disease progression after achieving either response or stable disease for at least 6 months from a previous treatment with erlotinib (Tarceva®) or gefitinib (Iressa®)
4. Patients aged 18 years or older
5. Life expectancy of at least three (3) months
6. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0-2
7. Written informed consent that is consistent with ICH-GCP guidelines

Exclusion criteria:

1. Prior major surgery, chemotherapy or radiation therapy within 4 weeks before start of therapy.
2. Prior treatment with an mTOR inhibitor within the past 4 weeks before start of therapy or concomitantly with this study
3. Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within 14 days of run-in treatment with Sirolimus
4. Active CNS metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants or steroids)
5. Severe alteration in serum fasting cholesterol (equal or more than 350 mg/dL) or triglycerides (equal or more than 400 mg/dL). Patients may be allowed to enrol on the trial after initiation of lipid lowering agents.

6. Requirement for treatment with any of the prohibited concomitant medications:

   • Concomitant CYP3A4 inhibitors within the past 7 days before start of therapy or concomitantly with this study.
   • Concomitant CYP3A4 inducers within the past 14 days before start of therapy or concomitantly with this study.
7. Any contraindications for therapy with Sirolimus.
8. Known hypersensitivity to BIBW 2992, Sirolimus or other rapamycin analogues (everolimus, temsirolimus, deforolimus, etc.) or the excipients of any of the trial drugs.
9. Use of any investigational drug within 4 weeks before start of therapy.