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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00993499
First received: October 8, 2009
Last updated: September 4, 2015
Last verified: September 2015
  Purpose

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.


Condition Intervention Phase
Carcinoma, Non-Small-Cell Lung
Drug: BIBW 2992
Drug: Sirolimus (rapamycin)
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Occurrence of Dose Limiting Toxicities (DLT) [ Time Frame: 2 first cycles, 56 days ] [ Designated as safety issue: No ]
    Number of participants with of dose limiting toxicities (DLT)


Secondary Outcome Measures:
  • Best Overall Response [ Time Frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days ] [ Designated as safety issue: No ]
    Best overall response (unconfirmed) according to RECIST v1.1

  • Objective Response [ Time Frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days ] [ Designated as safety issue: No ]
    Rate of (unconfirmed) objective response, defined as complete response (CR) or partial response (PR) according to RECIST v1.1

  • Rate of Disease Control [ Time Frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days ] [ Designated as safety issue: No ]
    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. [ Time Frame: Multiple time points during the trial ] [ Designated as safety issue: No ]

    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) [ Time Frame: 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib ] [ Designated as safety issue: No ]
    Maximum measured plasma concentration of Afatinib at steady state (Cmax,ss)

  • AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) [ Time Frame: 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    Maximum measured plasma concentration of sirolimus at steady state (Cmax,ss)

  • AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days ] [ Designated as safety issue: No ]
    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 [ Time Frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days ] [ Designated as safety issue: No ]
    Percentage of patients with drug-related adverse events (AEs).

  • Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin [ Time Frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days ] [ Designated as safety issue: No ]
    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.


Enrollment: 44
Study Start Date: October 2009
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BIBW 2992 + Sirolimus
Dose escalation of the combination BIBW 2992 plus Sirolimus.
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00993499

Locations
Spain
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
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00993499     History of Changes
Other Study ID Numbers: 1200.70  2009-010432-18 
Study First Received: October 8, 2009
Results First Received: September 4, 2015
Last Updated: September 4, 2015
Health Authority: Spain: Spanish Agency of Medicines

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Disease Progression
Bronchial Neoplasms
Carcinoma, Bronchogenic
Disease Attributes
Lung Diseases
Lung Neoplasms
Neoplasms
Neoplasms by Site
Pathologic Processes
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Everolimus
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on May 02, 2016