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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase Ib Open Label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Sirolimus in Patients With Non-small Cell Lung Cancer Harbouring an EGFR Mutation and/or Disease Progression Following Prior Erlotinib or Gefitinib

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BIBW 2992
* Drug: Sirolimus (rapamycin)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologically or cytologically confirmed diagnosis of Stage IIIB or Stage IV NSCLC Patients who have failed conventional treatment (at least 1 prior treatment line), or for whom no therapy of proven efficacy exists 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®) Patients aged 18 years or older Life expectancy of at least three (3) months Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0-2 Written informed consent that is consistent with ICH-GCP guidelines Exclusion criteria: Prior major surgery, chemotherapy or radiation therapy within 4 weeks before start of therapy. Prior treatment with an mTOR inhibitor within the past 4 weeks before start of therapy or concomitantly with this study Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within 14 days of run-in treatment with Sirolimus Active CNS metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants or steroids) 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. 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. Any contraindications for therapy with Sirolimus. Known hypersensitivity to BIBW 2992, Sirolimus or other rapamycin analogues (everolimus, temsirolimus, deforolimus, etc.) or the excipients of any of the trial drugs. Use of any investigational drug within 4 weeks before start of therapy.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992 + Sirolimus<br>Dose escalation of the combination BIBW 2992 plus Sirolimus. | Drug: BIBW 2992<br>* Dose escalation (19-40 patients): low or high dose oral + 12 addit. pat. at MTD, until progression or undue AEs<br>Drug: Sirolimus (rapamycin)<br>* Dose escalation (19-40 patients): several dose levels + 12 addit. pat. at MTD until progression or undue AEs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Dose Limiting Toxicities (DLT) | Number of participants with of dose limiting toxicities (DLT) | 2 first cycles, 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | Best overall response (unconfirmed) according to RECIST v1.1 | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | 
| Objective Response | Rate of (unconfirmed) objective response, defined as complete response (CR) or partial response (PR) according to RECIST v1.1 | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | 
| Rate of Disease Control | Rate of (unconfirmed) disease control defined as CR, PR, or stable disease (SD), according to RECIST v1.1 | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | 
| Exploratory Examination of EGFR Mutations (Exons 19, 20 and 21 and Others) in Serum/Plasma DNA and Tumour DNA. | Exploratory examination of Epidermal growth factor (receptor)(EGFR) mutations (Exons 19, 20 and 21 and others) in serum/plasma DNA and tumour DNA. This endpoint was not analysed in the study report as the available data was too limited. | Multiple time points during the trial | 
| Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss) | Maximum measured plasma concentration of Afatinib at steady state (Cmax,ss) | 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib | 
| AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) | Area under the curve (AUC) of Afatinib at steady state over the dosing interval τ (AUCτ,ss) for afatinib. | 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib | 
| Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Maximum measured plasma concentration of sirolimus at steady state (Cmax,ss) | 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib | 
| AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Area under the curve (AUC) of sirolimus at steady state over the dosing interval τ (AUCτ,ss) for afatinib. | 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib | 
| Occurrence of Adverse Events According to CTCAE, Version 3.0 | Percentage of participants with adverse events according to highest Common Terminology Criteria for Adverse Events (CTCAE) grade, version 3.0 | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | 
| Percentage of Patients With Drug-related AEs | Percentage of patients with drug-related adverse events (AEs). | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | 
| Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | Evaluation of laboratory parameters included assessment of the frequency of patients with ALT and AST elevations concurrent with elevated bilirubin and indicative of Hy's law cases. | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days |