Erlotinib Hydrochloride in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Completely Removed by Surgery (An ALCHEMIST Treatment Trial)

• ClinicalTrials.gov Identifier: NCT02193282
• Recruitment Status: Active, not recruiting
• First Posted: July 17, 2014
• Last Update Posted: February 13, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: July 15, 2014
• First Posted Date: July 17, 2014
• Last Update Posted Date: February 13, 2023
• Actual Study Start Date: August 18, 2014
• Estimated Primary Completion Date: October 10, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 22, 2017)

Overall survival (OS) [ Time Frame: The time from randomization until death, assessed up to 10 years ]

Estimated using the method of Kaplan-Meier survival curves and a 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare OS between the two arms. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess whether the distribution of OS times differ with respect to treatment regimen after having adjusted for the stratification factors as well as other potential prognostic and treatment covariates.

Original Primary Outcome Measures (submitted: July 15, 2014)

OS [ Time Frame: The time from randomization until death, assessed up to 5 years ]

Estimated using the method of Kaplan-Meier survival curves and a 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare OS between the two arms. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess whether the distribution of OS times differ with respect to treatment regimen after having adjusted for the stratification factors as well as other potential prognostic and treatment covariates.

Current Secondary Outcome Measures (submitted: February 14, 2019)

• Disease free survival (DFS) rate [ Time Frame: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed at 2 years ]
  DFS will be defined as the proportion of patients alive and disease free at 2 years from the date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.
• Overall survival (OS) rate at 5 years [ Time Frame: At 5 years ]
  Will be defined as the proportion of patients alive at 5 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.
• Overall survival (OS) rate at 10 years [ Time Frame: At 10 years ]
  Will be defined as the proportion of patients alive at 10 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.
• Overall disease free survival (DFS) between the erlotinib hydrochloride and observation arms [ Time Frame: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed up to 10 years ]
  Estimated using the method of Kaplan-Meier survival curves (21). A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.
• Incidence of adverse events associated with each treatment arm [ Time Frame: Up to 10 years ]
  The maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. All adverse events analysis will entail comparisons between the arms within Arms A and B, respectively. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.

Original Secondary Outcome Measures (submitted: July 15, 2014)

• DFS rate defined as the proportion of patients alive and disease free at 2 years from the date of randomization [ Time Frame: At 2 years ]
  Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.
• OS rate defined as the proportion of patients alive at 5 years from date of randomization [ Time Frame: At 5 years ]
  Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.
• Incidence of adverse events associated with each treatment arm [ Time Frame: Up to 5 years ]
  The maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. All adverse events analysis will entail comparisons between the arms within Arms I and II, respectively. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Erlotinib Hydrochloride in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Completely Removed by Surgery (An ALCHEMIST Treatment Trial)
• Official Title: Randomized Study of Erlotinib vs Observation in Patients With Completely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)
• Brief Summary: This phase III ALCHEMIST trial studies how well erlotinib hydrochloride compared to observation works in treating patients with stage IB-IIIA non-small cell lung cancer that has been completely removed by surgery (resected). Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVE:

I. To assess whether adjuvant therapy with erlotinib hydrochloride (erlotinib) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy.

SECONDARY OBJECTIVES:

I. To assess whether adjuvant therapy with erlotinib will result in improved disease free survival (DFS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA EGFR mutant NSCLC (confirmed centrally) following complete resection and standard post-operative therapy, both overall and within the stage subgroups: IB and II/IIIA.

II. To evaluate the safety profile of erlotinib in the adjuvant setting. III. To assess whether adjuvant therapy with erlotinib will result in improved DFS rate at 2 years, and OS rate at 5 and 10 years over observation for patients with completely resected stage IB (>= 4 cm)-IIIA EGFR mutant NSCLC (confirmed centrally) following complete resection and standard post-operative therapy, both overall and within the stage subgroups: IB and II/IIIA.

IV. To assess the primary and secondary objectives in all randomized patients, regardless of central confirmation of the EGFR mutant status.

V. To study detection of circulating EGFR mutations in cell-free plasma deoxyribonucleic acid (DNA) as a prognostic marker in resected early stage NSCLC.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM A (BLINDED ERLOTINIB- CLOSED 06/14/17): Blinded patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM B (PLACEBO- CLOSED 06/14/17): Patients receive placebo PO QD on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM C (UNBLINDED ERLOTINIB): Unblinded patients receive erlotinib hydrochloride PO QD on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM D (OBSERVATION): Patients (including patients previously randomized to placebo) undergo observation at least every 6 months for 2 years.

After completion of study treatment, patients are followed up every 6 months for 4 years and then yearly for 6 years.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

As of June 15, 2017, sites will sign into RAVE to unblind any patients that had previously enrolled

Primary Purpose: Treatment

Condition

• Lung Non-Squamous Non-Small Cell Carcinoma
• Stage IB Lung Non-Small Cell Carcinoma AJCC v7
• Stage II Lung Non-Small Cell Cancer AJCC v7
• Stage IIA Lung Non-Small Cell Carcinoma AJCC v7
• Stage IIB Lung Non-Small Cell Carcinoma AJCC v7
• Stage IIIA Lung Non-Small Cell Cancer AJCC v7

Intervention

• Other: Clinical Observation
  Undergo observation
  Other Name: observation
• Drug: Erlotinib Hydrochloride
  Given PO
  Other Names:

  • Cp-358,774
  • OSI-774
  • Tarceva
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Placebo Administration
  Given PO

Study Arms

• Experimental: Arm A (blinded erlotinib hydrochloride)
  Blinded patients receive erlotinib hydrochloride PO QD on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. (CLOSED 06/14/17)
  Interventions:

  • Drug: Erlotinib Hydrochloride
  • Other: Laboratory Biomarker Analysis
• Placebo Comparator: Arm B (placebo)
  Patients receive placebo PO QD on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. (CLOSED 06/14/17)
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Placebo Administration
• Experimental: Arm C (unblinded erlotinib hydrochloride)
  Unblinded patients receive erlotinib hydrochloride PO QD on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Erlotinib Hydrochloride
  • Other: Laboratory Biomarker Analysis
• Active Comparator: Arm D (observation)
  Patients (including patients previously randomized to placebo) undergo observation at least every 6 months for 2 years.
  Interventions:

  • Other: Clinical Observation
  • Other: Laboratory Biomarker Analysis

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 15, 2014): 450
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 10, 2026
• Estimated Primary Completion Date: October 10, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria:

  1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory

  2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results

     • Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible
     • Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105
• Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer
• Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration
• Non-pregnant and non-lactating
• No history of cornea abnormalities
• Granulocytes >= 1,500/ul
• Platelets >= 100,000/ul
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN
• Serum creatinine =< 1.5 x ULN

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT02193282
• Other Study ID Numbers: NCI-2014-01508; NCI-2014-01508 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); s16-02079; CALGB A081105; A081105 ( Other Identifier: Alliance for Clinical Trials in Oncology ); A081105 ( Other Identifier: CTEP ); U10CA180821 ( U.S. NIH Grant/Contract ); U10CA180830 ( U.S. NIH Grant/Contract ); U10CA031946 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ramaswamy Govindan; Alliance for Clinical Trials in Oncology

• PRS Account: National Cancer Institute (NCI)
• Verification Date: January 2023