Genetic Testing in Screening Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

Study Overview
=================
Brief Summary
-----------------
This ALCHEMIST trial studies genetic testing in screening patients with stage IB-IIIA non-small cell lung cancer that has been or will be removed by surgery. Studying the genes in a patient's tumor cells may help doctors select the best treatment for patients that have certain genetic changes.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To centrally test resected non-small cell lung cancer (NSCLC) for genetic mutations to facilitate accrual to randomized adjuvant studies. II. To obtain clinically annotated tumor tissue and patient-matched non-malignant deoxyribonucleic acid (DNA) from peripheral blood, as well as detailed epidemiologic and clinical follow-up data, to allow clinically annotated advanced genomic analyses in concert with the National Cancer Institute (NCI) Center for Cancer Genomics (CCG). SECONDARY OBJECTIVES: I. To characterize the natural history of molecularly characterized NSCLC to allow subsequent development of targeted therapies against genotype-defined subpopulations in the adjuvant and recurrent settings. II. To cross-validate local genotyping assays for EGFR and ALK and PD-L1 immunohistochemistry (IHC) with a central reference standard, when available. EXPLORATORY/OTHER OBJECTIVES: I. To study the genomic evolution of lung cancers by comparing genomic characteristics at resection and at recurrence. II. To understand reasons behind lack of enrollment to adjuvant targeted therapy studies for potentially eligible patients. III. To study the clinical significance of circulating tumor DNA within the plasma cell-free DNA (cfDNA) from early stage lung cancer patients. IV. To perform proteomic analyses on lung cancer specimens obtained at the time of resection (to identify prognostic biomarkers). OUTLINE: STEP 1 (SCREENING): Patients undergo collection of blood and tissue samples for EGFR, ALK, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1)/cytotoxic t-lymphocyte-associated protein 4 (CTLA-4) testing via direct sequencing, fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Patients that have had surgery prior to pre-registration will submit samples from the previous surgery for testing. STEP 2 (TREATMENT): Patients with a mutation targeted by one or more of the investigational drugs used in this study or those without mutations are assigned to 1 of 4 treatment subprotocols. A081105: 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. E4512: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive crizotinib PO twice daily (BID) 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: Patients undergo observation. EA5142: Patients are randomized to 1 of 2 arms. ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or positron emission tomography (PET)/CT throughout the trial and blood samples collection during screening and follow-up. ARM II: Patients are followed serially with CT and/or PET/CT imaging for up to 1 year. Patients also undergo blood sample collection during screening and follow-up. A081801: Patients are randomized to 1 of 3 arms. ARM A: INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then undergo observation. ARM B: INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab intravenously (IV) over 25-40 minutes on day 1. Treatment repeats every 21 days for 17 cycles in the absence of disease progression or unacceptable toxicity. ARM C: INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice and pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 13 cycles in the absence of disease progression or unacceptable toxicity. *ACCEPTABLE REGIMENS: DOUBLET I: Patients receive cisplatin IV over 1-2 hours and pemetrexed IV over 10 minutes on day 1 of each cycle. DOUBLET II: Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes on day 1 of each cycle. DOUBLET III: Patients receive cisplatin IV over 1-2 hours on day 1 of each cycle and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 of each cycle. DOUBLET IV: Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1 of each cycle. After completion of study, patients that are not enrolled on either A081105, E4512, EA5142, or A081801 are followed up every 6 months for 5 years.

Official Title
-----------------
Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST)

Conditions
-----------------
Stage IIA Lung Cancer AJCC v8, Stage IIB Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8

Intervention / Treatment
-----------------
* Procedure: Biospecimen Collection
* Drug: Carboplatin
* Drug: Cisplatin
* Other: Clinical Observation
* Procedure: Computed Tomography
* Drug: Crizotinib
* Other: Cytology Specimen Collection Procedure
* Drug: Erlotinib
* Drug: Gemcitabine Hydrochloride
* Biological: Nivolumab
* Drug: Paclitaxel
* Biological: Pembrolizumab
* Drug: Pemetrexed
* Drug: Pemetrexed Disodium
* Other: Placebo Administration
* Procedure: Positron Emission Tomography


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PATIENT PRE-REGISTRATION ELIGIBILITY CRITERIA: For pre-surgical patients Suspected diagnosis of resectable non-small cell lung cancer; cancers with a histology of adenosquamous are considered a type of adenocarcinoma and thus a nonsquamous histology; patients with squamous cell carcinoma are eligible Suspected clinical stage of IIIA, II (IIA or IIB) or large IB (defined as size >= 4 cm); Note: IB tumors < 4 cm are NOT eligible; stage IB cancer based on pleural invasion is not eligible unless the tumor size is >= 4 cm; the 7th edition of American Joint Committee on Cancer (AJCC) staging will be utilized For post-surgical patients Completely resected non-small cell lung cancer with negative margins (R0); patients with squamous cell carcinoma are eligible only if they have not received adjuvant therapy Pathologic stage IIIA, II (IIA or IIB) or large IB (defined as size >= 4 cm); Note: IB tumors < 4 cm are NOT eligible; stage IB cancer based on pleural invasion is not eligible unless the tumor size is >= 4 cm; the 7th edition of AJCC staging will be utilized Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Age ≥ 18 years No patients who have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer 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 year prior to registration No prior treatment with agents targeting EGFR mutation, ALK rearrangement, and PD-1/PD-L1/CTLA-4 No patients known to be pregnant or lactating Patients who have had local genotyping are eligible, regardless of the local result No patients with recurrence of lung cancer after prior resection Note: Post-surgical patients should proceed to registration immediately following preregistration PATIENT REGISTRATION ELIGIBILITY CRITERIA: Tissue available for the required analyses (either clinical tissue block or slides and scrolls) Completely resected NSCLC with negative margins (R0); cancers with a histology of adenosquamous are considered a type of adenocarcinoma and thus a nonsquamous histology Pathologic stage IIIA, IIA or IIB, or large IB (defined as size >= 4 cm); Note: IB tumors < 4 cm are NOT eligible; stage IB cancer based on pleural invasion is not eligible unless the tumor size is >= 4 cm; the 7th edition of AJCC staging will be utilized Patients with squamous cell carcinoma are eligible only if they have not received adjuvant therapy In order to allow for time for central genotyping and eligibility for the ALCHEMIST treatment trial, patients must register within the following eligibility windows: Squamous patients: No adjuvant therapy permitted, register patient within 77 days following surgery Non-squamous patients: If no adjuvant therapy, register patient within 75 days following surgery If adjuvant chemotherapy or radiotherapy only, register patient within 225 days following surgery If adjuvant chemotherapy and radiation, register patient within 285 days following surgery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A081105 Arm A (blinded erlotinib hydrochloride)<br>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) | Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;|
| Placebo Comparator: A081105 Arm B (placebo)<br>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) | Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;Other: Placebo Administration<br>* Given PO<br>|
| Experimental: A081105 Arm C (unblinded erlotinib hydrochloride)<br>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. | Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;Drug: Erlotinib<br>* Given PO<br>|
| Active Comparator: A081105 Arm D (observation)<br>Patients (including patients previously randomized to placebo) undergo observation at least every 6 months for 2 years. | Other: Clinical Observation<br>* Undergo observation<br>* Other names: observation;Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;|
| Active Comparator: A081801 Arm A (platinum doublet, observation)<br>INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then undergo observation. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Clinical Observation<br>* Undergo observation<br>* Other names: observation;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;|
| Experimental: A081801 Arm B (platinum doublet, sequential pembrolizumab)<br>INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 17 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;|
| Experimental: A081801 Arm C (platinum doublet, combination pembrolizumab)<br>INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens based on the treating physician's choice and pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 13 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;|
| Experimental: E4512 Arm A (crizotinib)<br>Patients receive crizotinib PO BID on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. | Drug: Crizotinib<br>* Given PO<br>* Other names: Xalkori;Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;|
| Active Comparator: E4512 Arm B (observation)<br>Patients undergo observation. | Other: Clinical Observation<br>* Undergo observation<br>* Other names: observation;Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;|
| Experimental: EA5142 Arm I (nivolumab)<br>Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or positron emission tomography (PET)/CT throughout the trial and blood samples collection during screening and follow-up. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT or PET/CT<br>* Other names: tomography;Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;|
| Active Comparator: EA5142 Arm II (observation)<br>Patients are followed serially with CT and/or PET/CT imaging for up to 1 year. Patients also undergo blood sample collection during screening and follow-up. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT or PET/CT<br>* Other names: tomography;Other: Cytology Specimen Collection Procedure<br>* Undergo collection of blood and tissue<br>* Other names: Cytologic Sampling;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central and local clinical genotyping to facilitate accrual to the adjuvant Intergroup studies, E4512 and A081105 | Central and local clinical genotyping to facilitate accrual to the adjuvant Intergroup studies, E4512 and A081105, will be measured by the rate of accrual. | Up to 4 years | 
| Feasibility of research grade formalin-fixed, paraffin-embedded tissue collection for Center for Cancer Genomics (CCG) analysis | Research grade formalin-fixed, paraffin-embedded tissue collection for Center for CCG analysis, will be measured by adequate specimens collected per month. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) rate for lung cancers which are wild-type for EGFR and ALK | Using genomics performed at CCG, DFS rate will be calculated for each genotype-defined population constituting greater than 1% of the study cohort. | Time from resection to the earliest of documented disease recurrence confirmed by biopsy, development of a new lung cancer confirmed by biopsy, or death from any cause, assessed at 2 years | 
| Agreement of local genotyping methods (direct sequencing of EGFR, ALK fluorescence in situ hybridization [FISH]) with central Clinical Laboratory Improvement Amendments genotyping | For each locally used assay, agreement will be defined as the proportion of patients deemed mutant (or wild-type) by local and central assessment divided by the number of evaluable patients, where an evaluable patient is one who has a local assessment result and has submitted tissue for central assessment. An agreement rate of 90% or higher between the local assay and the central assessment will be deemed acceptable. | Up to 5 years |