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

Boehringer Ingelheim44 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

BIBW 2992DRUG

Dose escalation (19-40 patients): low or high dose oral + 12 addit. pat. at MTD, until progression or undue AEs

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (8)

1200.70.34001 Boehringer Ingelheim Investigational Site

Badalona (Barcelona), Spain

1200.70.34008 Boehringer Ingelheim Investigational Site

Barcelona, Spain

1200.70.34009 Boehringer Ingelheim Investigational Site

Barcelona, Spain

1200.70.34006 Boehringer Ingelheim Investigational Site

Girona, Spain

1200.70.34007 Boehringer Ingelheim Investigational Site

L'Hospitalet de Llobregat (Barcelona), Spain

1200.70.34005 Boehringer Ingelheim Investigational Site

Majadahonda (Madrid), Spain

1200.70.34004 Boehringer Ingelheim Investigational Site

Valencia, Spain

1200.70.34002 Boehringer Ingelheim Investigational Site

Zaragoza, Spain

Outcomes

Primary Outcomes

Occurrence of Dose Limiting Toxicities (DLT)

Number of participants with of dose limiting toxicities (DLT)

Time frame: 2 first cycles, 56 days

Secondary Outcomes

Best Overall Response

Best overall response (unconfirmed) according to RECIST v1.1

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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)

Time frame: 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.

Time frame: 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)

Time frame: 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.

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

Time frame: 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).

Time frame: 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.

Time frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days