Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)

Advanced Malignant Solid Neoplasm Clinical Trial

Official title:

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of Tazemetostat in Patients With Tumors Harboring Alterations in EZH2 or Members of the SWI/SNF Complex

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03213665
• Other study ID #: NCI-2017-01245
• Secondary ID: NCI-2017-01245AP
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 13, 2017
• Est. completion date: September 22, 2024

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II Pediatric MATCH trial studies how well tazemetostat works in treating patients with brain tumors, solid tumors, non-Hodgkin lymphoma, or histiocytic disorders that have come back (relapsed) or do not respond to treatment (refractory) and have EZH2, SMARCB1, or SMARCA4 gene mutations. Tazemetostat may stop the growth of tumor cells by blocking EZH2 and its relation to some of the pathways needed for cell proliferation.

Description:

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with tazemetostat with advanced solid tumors (including central nervous system [CNS] tumors), non-Hodgkin lymphoma or histiocytic disorders that harbor gain of function mutations in EZH2, or loss of function mutations in the SWI/SNF complex subunits SMARCB1 or SMARCA4 at a dose of 520 mg/m^2/dose twice daily for patients without any CNS involvement or 1200 mg/m^2/dose orally twice daily for patients with CNS involvement. SECONDARY OBJECTIVES: I. To estimate the progression-free survival in pediatric patients treated with tazemetostat that harbor gain of function mutations in EZH2, or loss of function mutations in the SWI/SNF complex subunits SMARCB1 or SMARCA4. II. To obtain information about the tolerability of tazemetostat in children with relapsed or refractory cancer. EXPLORATORY OBJECTIVES: I. To evaluate other biomarkers as predictors of response to tazemetostat and specifically, whether tumors that harbor different missense mutations or fusions will demonstrate differential response to tazemetostat treatment. II. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA). OUTLINE: Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: September 22, 2024
• Est. primary completion date: March 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 21 Years

Eligibility

Inclusion Criteria:

• Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621C based on the presence of an actionable mutation
• Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than one slice; Note: The

following do not qualify as measurable disease:

• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive
• >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell Infusions (with or without total body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation; Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• Patients must not have had prior exposure to tazemetostat or other inhibitor(s) of EZH2
• For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70

ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

• Age 1 to < 2 years: male: 0.6 mg/dL; female: 0.6 mg/dL
• Age 2 to < 6 years: male: 0.8 mg/dL; female: 0.8 mg/dL
• Age 6 to < 10 years: male: 1 mg/dL; female: 1 mg/dL
• Age 10 to < 13 years: male: 1.2 mg/dL; female: 1.2 mg/dL
• Age 13 to < 16 years: male: 1.5 mg/dL; female: 1.4 mg/dL
• Age >= 16 years: male: 1.7 mg/dL; female: 1.4 mg/dL
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL
• Corrected QT (QTc) interval =< 480 milliseconds
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [V] 4.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
• International normalized ratio (INR) =< 1.5
• For subjects with CNS involvement (primary tumor or metastatic disease): Subjects must not have any active bleeding, or new intratumoral hemorrhage of more than punctate size on screening MRI or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study because there is currently no available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment; female subjects of childbearing potential should agree to remain abstinent or use adequate contraceptive methods for 30 days after the last dose of tazemetostat; male subjects should agree to remain abstinent or use adequate contraceptive methods, and agree to refrain from donating sperm, and for 90 days after the last dose of tazemetostat
• Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients who are currently receiving drugs that are strong inducers or strong inhibitors of CYP3A4 are not eligible; strong inducers or inhibitors of CYP3A4 are prohibited from 14 days prior to the first dose of tazemetostat to the end of the study; Note: Dexamethasone for CNS tumors or metastases, on a stable dose, is allowed
• Patients who have an uncontrolled infection are not eligible
• On complete blood count (CBC) differential, patients must not have any significant morphologic abnormalities concerning for myeloproliferative neoplasm (MPN)/myelodysplastic syndrome (MDS) or T- acute lymphoblastic leukemia (ALL)
• Patients must not have thrombocytopenia, neutropenia, or anemia of grade >= 3 (per CTCAE 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)
• Patients with a history of prior history of T-lymphoblastic lymphoma (LBL)/T-ALL
• Patients with any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
• Patients who have received prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Related Conditions & MeSH terms

• Advanced Malignant Solid Neoplasm
• Ann Arbor Stage III Hodgkin Lymphoma
• Ann Arbor Stage III Non-Hodgkin Lymphoma
• Ann Arbor Stage IV Hodgkin Lymphoma
• Ann Arbor Stage IV Non-Hodgkin Lymphoma
• Central Nervous System Neoplasms
• Ependymoma
• Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• Glioma
• Hepatoblastoma
• Histiocytosis
• Histiocytosis, Langerhans-Cell
• Hodgkin Disease
• Low Grade Glioma
• Lymphoma
• Lymphoma, Non-Hodgkin
• Medulloblastoma
• Neoplasms
• Neoplasms, Germ Cell and Embryonal
• Nervous System Neoplasms
• Neuroblastoma
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Neuroectodermal Tumors, Primitive, Peripheral
• Osteosarcoma
• Recurrence
• Recurrent Ependymoma
• Recurrent Ewing Sarcoma
• Recurrent Glioma
• Recurrent Hepatoblastoma
• Recurrent Hodgkin Lymphoma
• Recurrent Langerhans Cell Histiocytosis
• Recurrent Malignant Germ Cell Tumor
• Recurrent Malignant Glioma
• Recurrent Malignant Solid Neoplasm
• Recurrent Medulloblastoma
• Recurrent Neuroblastoma
• Recurrent Non-Hodgkin Lymphoma
• Recurrent Osteosarcoma
• Recurrent Peripheral Primitive Neuroectodermal Tumor
• Recurrent Primary Central Nervous System Neoplasm
• Recurrent Rhabdoid Tumor
• Recurrent Rhabdomyosarcoma
• Recurrent Soft Tissue Sarcoma
• Refractory Hodgkin Lymphoma
• Refractory Langerhans Cell Histiocytosis
• Refractory Malignant Germ Cell Tumor
• Refractory Malignant Glioma
• Refractory Malignant Solid Neoplasm
• Refractory Medulloblastoma
• Refractory Neuroblastoma
• Refractory Non-Hodgkin Lymphoma
• Refractory Osteosarcoma
• Refractory Peripheral Primitive Neuroectodermal Tumor
• Refractory Rhabdoid Tumor
• Refractory Soft Tissue Sarcoma
• Rhabdoid Tumor
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing
• Stage III Soft Tissue Sarcoma AJCC v7
• Stage IV Soft Tissue Sarcoma AJCC v7
• Wilms Tumor

Intervention

Drug:
• Tazemetostat
Given PO

Locations

Country	Name	City	State
Puerto Rico	San Jorge Children's Hospital	San Juan
Puerto Rico	University Pediatric Hospital	San Juan
United States	Albany Medical Center	Albany	New York
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of Rochester	Rochester	New York
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	Children's Oncology Group

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarker Predictors of Response to Tazemetostat	Will evaluate other biomarkers as predictors of response to tazemetostat and specifically, whether tumors that harbor different missense mutations or fusions will demonstrate differential response to tazemetostat treatment. Will be performed and will be summarized with simple summary statistics and will be descriptive in nature.	Up to 2 years
Other	Change in Tumor Genomics	To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid. Will be performed and will be summarized with simple summary statistics and will be descriptive in nature.	Up to 2 years
Primary	Objective Response Rate (ORR)	ORR will be defined as complete response + partial response and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method.	From enrollment to the end of treatment, up to 2 years
Secondary	Progression-free Survival (PFS)	Progression free survival will be defined as time from the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause. PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.	From start of subprotocol treatment to time of progression or death, whichever occurs first, assessed for up to 2 years
Secondary	Percentage of Patients Experiencing Grade 3 or 4 Adverse Events	Will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Any eligible patient who receives at least one dose of protocol therapy will be considered in the evaluation of toxicity. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient.	From initiation of treatment to disease progression, disease recurrence, or death from any cause assessed up to 2 years