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Erlotinib Therapy and Subsequent Development of Mechanisms of Secondary Resistance in Patients With NSCLC

This study has been completed.
Sponsor:
Collaborators:
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Genentech, Inc.
Information provided by (Responsible Party):
David M. Jackman, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT00997334
First received: October 16, 2009
Last updated: February 28, 2017
Last verified: February 2017
  Purpose
Erlotinib is a drug which targets non small cell lung cancer with a genetic change (mutation) in the epidermal growth factor receptor (EGFR). This drug has been used in other cancer research studies and information from those studies suggests that Erlotinib can control the growth of these cancer cells.

Condition Intervention Phase
Non-small Cell Lung Cancer Drug: Erlotinib Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: First-Line Erlotinib Therapy and the Subsequent Development of Mechanisms of Secondary Resistance in Patients With Non-Small Cell Lung Cancer and Known Sensitizing EGFR Mutations

Resource links provided by NLM:


Further study details as provided by David M. Jackman, MD, Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Resistance Mechanism [ Time Frame: Participants were evaluated for incidence of genetic mechanisms of secondary resistance at time of disease progression at which point participants stopped treatment. Progression follow up was up to 3 years in this study cohort. ]
    Participants were classified into 4 potential resistant mechanism groups (4 genetic/ 1 histologic) based on evaluation of rebiopsy tissue: EGFR mutations (T790M mutation, exon 20 insertion), KRAS mutations, MET amplification or small-cell lung cancer (SCLC) transform using established methods.


Secondary Outcome Measures:
  • Progression-Free Survival [ Time Frame: Disease was evaluated radiologically every 8 weeks on treatment (cycle duration=4 weeks). Participants were treated until evidence of disease progression or unacceptable toxicity. Progression follow-up was up to 3 years in this study cohort. ]
    Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.


Enrollment: 60
Actual Study Start Date: February 2010
Study Completion Date: January 2017
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Erlotinib
Erlotinib was given at a dose of 150mg orally once per day for 28 days (+/- 3 days); Patients are treated until disease progression or until unaccepted drug toxicity.
Drug: Erlotinib
Other Name: Tarceva

Detailed Description:

PRIMARY OBJECTIVE

-To prospectively assess the frequency of different genetic mechanisms of secondary resistance in patients' tumors during treatment with erlotinib (e.g., T790M mutations, MET amplification).

  • Correlate these genetic changes with patient demographic data and clinical outcomes (time to progression, survival, sites of recurrence/progression).
  • Search for novel mechanisms of acquired resistance to erlotinib.
  • Identify whether these genetic changes are present at low levels in initial pretreatment tumor specimens.

SECONDARY OBJECTIVE(S)

  1. To measure the steady-state plasma concentrations of erlotinib during the course of patients' treatment.

    • Determine if the development and/or resolution of skin toxicity is related to plasma erlotinib concentrations.
    • Determine if the development of disease progression while on erlotinib is correlated with declines in plasma erlotinib concentrations.
    • Assess the plasma levels in patients whose smoking status has been biochemically verified to determine if smoking is associated with lower erlotinib plasma concentration.
  2. To analyze from both free plasma DNA and DNA from circulating tumor cells of erlotinib-treated patients for the original sensitizing EGFR mutations and genetic changes associated with secondary resistance.
  3. To measure clinical outcomes in patients with known sensitizing mutations in their tumor EGFR when treated with first-line erlotinib.

    • Response rate
    • Time to progression
    • Median overall survival
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed non-small cell lung cancer, stage IV or IIIB with a malignant pleural or pericardial effusion. Patients with stage I or II non-small cell lung cancer who have undergone surgical resection but who subsequently relapse with metastatic disease or a malignant pleural effusion are also eligible.
  • Documentation of a sensitizing mutation of the epidermal growth factor receptor. In addition, there must be a sufficient tissue for analysis of KRAS (the oncogene from the Kirsten rat sarcoma virus) mutations and MET amplification.
  • At least one measurable or evaluable site of disease as defined by revised RECIST (version 1.1) criteria.
  • 18 years of age or older
  • No more than one prior systemic therapy regimen for advanced non-small cell lung cancer. Chemotherapy delivered as part of concurrent chemoradiation will also count as a prior systemic therapy regimen. Adjuvant therapy for resected NSCLC will not count towards this total as long as it was completed at least 6 months prior to enrollment and did not include therapy with an EGFR-targeted agent. Adjuvant therapy completed less than 6 months prior to the time of screening will count as a prior regimen.
  • 3 or more weeks since prior major surgery
  • 2 or more weeks since prior radiation
  • ECOG performance status 0-1
  • Life expectancy > 8 weeks
  • Adequate hematologic, renal, and hepatic function
  • Willingness to undergo repeat tumor biopsy at the time of disease progression.

Exclusion Criteria:

  • Untreated and/or uncontrolled central nervous system metastases. Patients with prior brain metastases must have had definitive treatment (radiation or surgery) and must be clinically stable off steroids for at least 1 week prior to enrollment.
  • More than one prior systemic chemotherapy for advanced non-small cell lung cancer. , Chemotherapy delivered as part of concurrent chemoradiation will also count as a prior systemic therapy regimen. Adjuvant therapy for resected NSCLC willnot count towards this total as long as it was completed at least 6 months prior to enrollment and did not include therapy with an EGFR-targeted agent. Adjuvant therapy completed less than 6 months prior to the time of screening will count as a prior regimen.
  • Prior exposure to erlotinib or other treatments targeting the HER family axis.
  • Active malignancies within the past 3 years, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
  • Any process that compromises the ability to swallow and/or absorb oral medication.
  • Incomplete healing from previous surgery
  • A history of any of the following autoimmune skin disorders: Sjogren's syndrome, scleroderma, dermatomyositis, and systemic lupus erythematosus.
  • Significant medical history or unstable medical conditions.
  • Concurrent use of warfarin. Patients must be off warfarin for at least one week prior to initiation of erlotinib. Other non-warfarin anticoagulants are permitted.
  • Patients who require ongoing concomitant use of one of the strong inhibitors/inducers of CYP3A4.
  • Pregnant or breastfeeding. Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation.
  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: NCT00997334

Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
David M. Jackman, MD
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Genentech, Inc.
Investigators
Principal Investigator: David Jackman, MD Dana-Farber Cancer Institute
  More Information

Additional Information:
Publications:
Responsible Party: David M. Jackman, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00997334     History of Changes
Other Study ID Numbers: 09-210
NE_OSI4590s ( Other Identifier: Genentech/Roche )
Study First Received: October 16, 2009
Results First Received: January 5, 2017
Last Updated: February 28, 2017
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by David M. Jackman, MD, Dana-Farber Cancer Institute:
erlotinib
EGFR mutation
NSCLC

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 21, 2017