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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

Primary Purpose

Carcinoma, Non-Small-Cell Lung

Status
Completed
Phase
Phase 1
Locations
Spain
Study Type
Interventional
Intervention
BIBW 2992
Sirolimus (rapamycin)
Sponsored by
Boehringer Ingelheim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Carcinoma, Non-Small-Cell Lung

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • 1200.70.34001 Boehringer Ingelheim Investigational Site
  • 1200.70.34008 Boehringer Ingelheim Investigational Site
  • 1200.70.34009 Boehringer Ingelheim Investigational Site
  • 1200.70.34006 Boehringer Ingelheim Investigational Site
  • 1200.70.34007 Boehringer Ingelheim Investigational Site
  • 1200.70.34005 Boehringer Ingelheim Investigational Site
  • 1200.70.34004 Boehringer Ingelheim Investigational Site
  • 1200.70.34002 Boehringer Ingelheim Investigational Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BIBW 2992 + Sirolimus

Arm Description

Dose escalation of the combination BIBW 2992 plus Sirolimus.

Outcomes

Primary Outcome Measures

Occurrence of Dose Limiting Toxicities (DLT)
Number of participants with of dose limiting toxicities (DLT)

Secondary Outcome Measures

Best Overall Response
Best overall response (unconfirmed) according to RECIST v1.1
Objective Response
Rate of (unconfirmed) objective response, defined as complete response (CR) or partial response (PR) according to RECIST v1.1
Rate of Disease Control
Rate of (unconfirmed) disease control defined as CR, PR, or stable disease (SD), according to RECIST v1.1
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.
Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss)
Maximum measured plasma concentration of Afatinib at steady state (Cmax,ss)
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.
Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss)
Maximum measured plasma concentration of sirolimus at steady state (Cmax,ss)
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
Percentage of Patients With Drug-related AEs
Percentage of patients with drug-related adverse events (AEs).
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.

Full Information

First Posted
October 8, 2009
Last Updated
September 4, 2015
Sponsor
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT00993499
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2015
Overall Recruitment Status
Completed
Study Start Date
October 2009 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim

4. Oversight

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Non-Small-Cell Lung

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BIBW 2992 + Sirolimus
Arm Type
Experimental
Arm Description
Dose escalation of the combination BIBW 2992 plus Sirolimus.
Intervention Type
Drug
Intervention Name(s)
BIBW 2992
Intervention Description
Dose escalation (19-40 patients): low or high dose oral + 12 addit. pat. at MTD, until progression or undue AEs
Intervention Type
Drug
Intervention Name(s)
Sirolimus (rapamycin)
Intervention Description
Dose escalation (19-40 patients): several dose levels + 12 addit. pat. at MTD until progression or undue AEs.
Primary Outcome Measure Information:
Title
Occurrence of Dose Limiting Toxicities (DLT)
Description
Number of participants with of dose limiting toxicities (DLT)
Time Frame
2 first cycles, 56 days
Secondary Outcome Measure Information:
Title
Best Overall Response
Description
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
Title
Objective Response
Description
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
Title
Rate of Disease Control
Description
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
Title
Exploratory Examination of EGFR Mutations (Exons 19, 20 and 21 and Others) in Serum/Plasma DNA and Tumour DNA.
Description
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
Title
Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss)
Description
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
Title
AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss)
Description
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
Title
Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss)
Description
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
Title
AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss)
Description
Area under the curve (AUC) of sirolimus at steady state over the dosing interval τ (AUCτ,ss) for afatinib.
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
Title
Occurrence of Adverse Events According to CTCAE, Version 3.0
Description
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
Title
Percentage of Patients With Drug-related AEs
Description
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
Title
Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boehringer Ingelheim
Organizational Affiliation
Boehringer Ingelheim
Official's Role
Study Chair
Facility Information:
Facility Name
1200.70.34001 Boehringer Ingelheim Investigational Site
City
Badalona (Barcelona)
Country
Spain
Facility Name
1200.70.34008 Boehringer Ingelheim Investigational Site
City
Barcelona
Country
Spain
Facility Name
1200.70.34009 Boehringer Ingelheim Investigational Site
City
Barcelona
Country
Spain
Facility Name
1200.70.34006 Boehringer Ingelheim Investigational Site
City
Girona
Country
Spain
Facility Name
1200.70.34007 Boehringer Ingelheim Investigational Site
City
L'Hospitalet de Llobregat (Barcelona)
Country
Spain
Facility Name
1200.70.34005 Boehringer Ingelheim Investigational Site
City
Majadahonda (Madrid)
Country
Spain
Facility Name
1200.70.34004 Boehringer Ingelheim Investigational Site
City
Valencia
Country
Spain
Facility Name
1200.70.34002 Boehringer Ingelheim Investigational Site
City
Zaragoza
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
28625629
Citation
Moran T, Palmero R, Provencio M, Insa A, Majem M, Reguart N, Bosch-Barrera J, Isla D, Costa EC, Lee C, Puig M, Kraemer S, Schnell D, Rosell R. A phase Ib trial of continuous once-daily oral afatinib plus sirolimus in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer and/or disease progression following prior erlotinib or gefitinib. Lung Cancer. 2017 Jun;108:154-160. doi: 10.1016/j.lungcan.2017.03.009. Epub 2017 Mar 22.
Results Reference
derived
Links:
URL
http://trials.boehringer-ingelheim.com/
Description
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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

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