Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer

Colon Adenocarcinoma Clinical Trial

Official title:

Randomized Trial of Consolidation Targeted Adjuvant Therapy With Encorafenib and Cetuximab Versus Usual Care for Patients With Stage II/III BRAF V600E Colon Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05710406
• Other study ID #: A022004
• Secondary ID: NCI-2022-09129
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: May 30, 2023
• Est. completion date: August 2034

Study information

• Verified date: April 2024
• Source: Alliance for Clinical Trials in Oncology
• Contact: Rona Yaeger, MD
• Phone: 646-888-5109
• Email: yaegerr[@]mskcc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.

Description:

The primary and secondary objectives of the study: PRIMARY OBJECTIVES: I. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III) SECONDARY OBJECTIVES: I. To evaluate and compare overall survival (OS) between the two treatment arms. II. To evaluate and compare the toxicity profile between the two treatment arms. III. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms. IV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms. EXPLORATORY OBJECTIVE: I. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up. ARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 394
• Est. completion date: August 2034
• Est. primary completion date: August 2034
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• PRE-REGISTRATION (STEP 0) ELIGIBILITY CRITERIA:
• BRAF V600 mutational status may be determined either locally or by central testing. This testing is mandatory prior to registration to determine eligibility. Tissue submission should be initiated as soon after surgery as possible. For tumors evaluated at local laboratories, formalin-fixed paraffin-embedded (FFPE) tumor tissue must still be submitted for central confirmation of BRAF status
• REGISTRATION (STEP 1) ELIGIBILITY CRITERIA:
• Histologically-proven stage III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk (pT4) stage II colon adenocarcinoma. Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve) and must have been completely resected
• BRAF V600E mutation
• MMR proficient (pMMR) or microsatellite stable (MSS) tumor
• Histologic documentation: adenocarcinoma
• Stage: III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk II (pT4)
• Tumor site: colon
• Patients must have received at least 3 months of adjuvant chemotherapy with either leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) (minimum of 5 cycles) or capecitabine and oxaliplatin (CAPOX) (minimum of 3 cycles)
• Adjuvant therapy must be completed at most 8 weeks prior to registration
• No other prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy) or radiation therapy for the current colon cancer is permitted
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Platelet count >= 75 x 10^9/L
• Hemoglobin > 9.0 g/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN
• Corrected QT (QTc) Interval =< 480 msec
• Creatinine = calculated (calc.) creatinine clearance >= 40 mL/min
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• No medical condition such as uncontrolled infection, uncontrolled diabetes mellitus, or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
• Patients with known history or current symptoms of cardiac disease or history of treatment with cardiotoxic agents in the last 12 months, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• No uncontrolled or poorly-controlled hypertension (> 180 mmHg systolic or > 130 mmHg diastolic)
• No history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab
• No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for >= 3 years
• Patients are not considered to have a "currently active" malignancy if they had a gastric or bowel carcinoid < 1 cm, ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS) of the breast without invasive cancer, or endometrial dysplasia/carcinoma in situ
• Patients are not considered to have a "currently active" malignancy if they had a sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was noninvasive
• No known medical condition causing an inability to swallow oral formulations of agents
• No residual Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 grade >= 2 toxicity from prior chemotherapy, with the exception of grade 2 alopecia or neuropathy
• Drugs that prolong the QTc interval should be avoided if possible, as encorafenib can prolong the QTc interval. Drugs that are generally accepted to have a risk of causing Torsades de Pointes should be discontinued or replaced with drugs that do not carry this risk if at all possible. Patients who receive potential QTc-prolonging medications should be monitored closely
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed during treatment on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed during treatment on this study. Patients must discontinue the drug 14 days prior to registration on the study Exclusion Criteria: N/A

Related Conditions & MeSH terms

• Colon Adenocarcinoma
• Colonic Neoplasms
• Stage IIB Colon Cancer AJCC v8
• Stage IIC Colon Cancer AJCC v8
• Stage III Colon Cancer AJCC v8

Intervention

Drug:
• Encorafenib
Given PO

Biological:
• Cetuximab
Given IV

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Computed Tomography
Undergo CT
• Magnetic Resonance Imaging
Undergo MRI

Other:
• Patient Observation
Undergo observation per usual care

Locations

Country	Name	City	State
United States	Hawaii Cancer Care - Westridge	'Aiea	Hawaii
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	ThedaCare Regional Cancer Center	Appleton	Wisconsin
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	ThedaCare Cancer Care - Berlin	Berlin	Wisconsin
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Aultman Health Foundation	Canton	Ohio
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Miami Valley Hospital South	Centerville	Ohio
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Northwest Cancer Center - Main Campus	Crown Point	Indiana
United States	Parkland Memorial Hospital	Dallas	Texas
United States	UT Southwestern Simmons Cancer Center - RedBird	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Blood and Cancer Center	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Northwest Oncology LLC	Dyer	Indiana
United States	Prisma Health Cancer Institute - Easley	Easley	South Carolina
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas
United States	Beebe South Coastal Health Campus	Frankford	Delaware
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Glens Falls Hospital	Glens Falls	New York
United States	Northwestern Medicine Glenview Outpatient Center	Glenview	Illinois
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Northwestern Medicine Grayslake Outpatient Center	Grayslake	Illinois
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Northwest Cancer Center - Hobart	Hobart	Indiana
United States	Saint Mary Medical Center	Hobart	Indiana
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	Cleveland Clinic Cancer Center Independence	Independence	Ohio
United States	Saint Catherine Hospital	Indianapolis	Indiana
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Community Medical Hospital	Missoula	Montana
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	The Community Hospital	Munster	Indiana
United States	Women's Diagnostic Center - Munster	Munster	Indiana
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	ThedaCare Regional Medical Center - Neenah	Neenah	Wisconsin
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Saint Alphonsus Medical Center-Ontario	Ontario	Oregon
United States	Northwestern Medicine Orland Park	Orland Park	Illinois
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Upstate Cancer Center at Oswego	Oswego	New York
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	UT Southwestern Clinical Center at Richardson/Plano	Richardson	Texas
United States	United Hospital	Saint Paul	Minnesota
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	North Coast Cancer Care	Sandusky	Ohio
United States	Community Medical Center	Scranton	Pennsylvania
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	ThedaCare Cancer Care - Shawano	Shawano	Wisconsin
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	SUNY Upstate Medical Center-Community Campus	Syracuse	New York
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Upper Valley Medical Center	Troy	Ohio
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	MGC Hematology Oncology-Union	Union	South Carolina
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	Northwest Cancer Center - Valparaiso	Valparaiso	Indiana
United States	Upstate Cancer Center at Verona	Verona	New York
United States	South Pointe Hospital	Warrensville Heights	Ohio
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	ThedaCare Cancer Care - Waupaca	Waupaca	Wisconsin
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	• Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events for symptoms of rash, diarrhea, and fatigue	summarized for each patient.	up to 6 years
Primary	Circulating tumor deoxyribonucleic acid (ctDNA) clearance rate (Phase II; ctDNA positive cohort)	defined as the proportion of patients with undetectable ctDNA status at 6 months after randomization among patients with detectable ctDNA status at randomization. The ctDNA clearance rate at 6 months after randomization in experimental arm will be compared to control arm by Chi-squared test. The one-sided p-value will be reported. Due to small sample size, Cochran and Mantel-Haenszel test, stratified by stratification factors will be performed as sensitivity analysis.	At 6 months after randomization
Primary	tDNA recurrence-free survival rate (ctDNA-RFS) (Phase II; ctDNA negative cohort)	Defined as the proportion of patients who remained undetectable ctDNA status, recurrence-free, and alive at 6 months after randomization among patients with undetectable ctDNA status at randomization. The ctDNA-RFS in experimental arm will be compared to control arm by Cochran and Mantel-Haenszel test, stratified by stratification factors. The one-sided p-value will be reported.	at 6 months after randomization
Primary	Disease free survival (DFS) (Phase III)	Defined as the time from the date of randomization to the date of first documented recurrence or death due to all cause, whichever occurs first. Patients without events observed at the end of the study will be censored at the date of last disease evaluation which shows no evidence of disease. At each analysis (Interim #1, Interim #2, and Final), stratified Cox model will be conducted to compare DFS in the experimental arm to DFS in the control arm with stratification factors as stratum, based on all data collected at the analysis time point.	Assessed up to 6 years after randomization
Secondary	Overall Survival	Defined as the time from the date of randomization to death due to all causes. The distributions of time-to-event endpoints will be estimated, in each arm, using the method of Kaplan-Meier and compared by a stratified Cox regression model.	Assessed up to 6 years
Secondary	Incidence of adverse events after randomization	The maximum grade for each type of adverse events that are possibly, probably, or definitely related to study treatments will be summarized for each patient. The frequency tables will be reviewed to determine the patterns. The overall adverse event rates for grade 4 or higher adverse events will be compared between two treatment groups using Chi-square test (or Fisher's exact test if the data in the contingency table is sparse).	up to 6 years
Secondary	Alternative disease free survival	Defined as the time from the date of primary tumor resection to the date of first documented recurrence or death due to all cause, whichever occurs first. The distributions of time-to-event endpoints will be estimated, in each arm, using the method of Kaplan-Meier and compared by a stratified Cox regression model.	assessed up to 6 years