A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis
- Conditions
- Recurrent Langerhans Cell HistiocytosisRefractory Langerhans Cell Histiocytosis
- Interventions
- Procedure: Biospecimen CollectionProcedure: Bone Marrow AspirationProcedure: Bone Marrow BiopsyProcedure: Computed TomographyProcedure: Echocardiography TestProcedure: FDG-Positron Emission Tomography and Computed Tomography ScanProcedure: Lumbar PunctureProcedure: Multigated Acquisition Scan
- Registration Number
- NCT05828069
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis that is growing, spreading, or getting worse (progressive), has come back (relapsed) after previous treatment, or does not respond to therapy (refractory). Langerhans cell histiocytosis is a type of disease that occurs when the body makes too many immature Langerhans cells (a type of white blood cell). When these cells build up, they can form tumors in certain tissues and organs including bones, skin, lungs and pituitary gland and can damage them. This tumor is more common in children and young adults. DAY101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Using DAY101 may be effective in treating patients with relapsed or refractory Langerhans cell histiocytosis.
- Detailed Description
PRIMARY OBJECTIVE:
I. To determine overall response rate (ORR) for children and young adults with relapsed or refractory BRAFV600E positive (cohort 1) and BRAFV600E negative (cohort 2) Langerhans cell histiocytosis (LCH) treated with tovorafenib (DAY101) after 2 cycles and must be maintained 4 weeks later.
SECONDARY OBJECTIVES:
I. To determine nature and severity of adverse events in patients treated with tovorafenib (DAY101) for relapsed or refractory LCH.
II. To describe event-free survival (EFS) at 1 year in children and young adults with relapsed and refractory LCH treated with tovorafenib (DAY 101) for up to 1 year.
III. To determine durability of response in children and young adults with relapsed or refractory LCH treated with tovorafenib (DAY101) following cessation of therapy in patients with complete response (CR) at 1 year.
IV. To describe progression-free (and relapse-free) survival (PFS) and overall survival (OS) in children and young adults with relapsed or refractory LCH treated with tovorafenib (DAY101) for up to 1 year.
EXPLORATORY OBJECTIVES:
I. To determine potential role of pathogenic tumor mutation in response to tovorafenib (DAY101), and to evaluate changes in bone marrow and peripheral blood cell populations carrying pathogenic mutations in response to tovorafenib (DAY101) therapy.
Ia. To define somatic mutations in LCH lesion biopsies; Ib. To determine impact of tovorafenib (DAY101) on bone marrow and blood BRAFV600E+ mononuclear cells; Ic. To determine impact of tovorafenib (DAY101) on cerebral spinal fluid and disease response; Id. To determine the performance of standardized immunohistochemical analysis of LCH lesion biopsies.
II. To compare performance of LCH-specific response criteria to Response Evaluation Criteria in Solid Tumors (RECIST).
III. To describe the pharmacokinetics of tovorafenib (DAY101) when administered to pediatric and young adult patients with relapse or refractory LCH.
OUTLINE: This is a dose escalation study of tovorafenib followed by a phase II trial.
Patients receive tovorafenib orally (PO) once weekly (QW) on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-gated acquisition (MUGA) or echocardiography (ECHO) scans, and fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) or computed tomography (CT) throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up.
After completion of study treatment, patients are followed up at 28 days, months 3, 6, 9, and 12, and then at 2 years post cycle 12.
Recruitment & Eligibility
- Status
- SUSPENDED
- Sex
- All
- Target Recruitment
- 48
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180 days- < 22 years (at time of study enrollment)
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Patient must have a body surface area of ≥ 0.3 m^2
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Patients with progressive, relapsed, or recurrent LCH with measurable disease at study entry
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Patients must have had histologic verification of LCH (from either original diagnosis or relapse/progression) at the time of study entry (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary)
- Tissue confirmation of relapse is recommended but not required
- Pathology report must be submitted for central confirmation of diagnosis within 7 days of enrollment.
- Formalin-fixed paraffin-embedded (FFPE) blocks or unstained slides (initial diagnosis and/or subsequent biopsies) will be required for retrospective central confirmation of diagnosis and molecular studies
- Patients with mixed histiocytic disorders (e.g. LCH with juvenile xanthogranuloma) may be included
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Patients must have measurable disease, documented by radiographic imaging (LCH- specific response criteria (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary).
-
Patients must have progressive or refractory disease or experience relapse after at least one previous systemic treatment strategy
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Pathogenic somatic mutation detected in genes encoding tyrosine kinase receptors (CSFR1, ERBB3 or ALK), RAS or RAF (may be from original or subsequent biopsy or peripheral blood/bone marrow aspirate). Clinical mutation reports may include quantitative polymerase chain reaction (PCR) (e.g. BRAFV600E) and/or Sanger or next generation sequencing. Immunohistochemistry (e.g. VE1 antibody for BRAFV600E) alone is not sufficient
-
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Participant must be able to take an enteral dose and formulation of medication. Study medication is only available as an oral suspension or tablet, which may be taken by mouth or other enteral route such as nasogastric, jejunostomy, or gastric tube
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Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50% for patients =< 16 years of age
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Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
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Myelosuppressive chemotherapy: Patients must not have received within 14 days of entry onto this study
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Investigational agent or any other anticancer therapy not defined above: Patients must not have received any investigational agent or any other anticancer therapy (including MAPK pathway inhibitor) for at least 14 days prior to planned start of tovorafenib (DAY101)
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Radiation therapy (RT): Patient must not have received RT within 2 weeks after the last dose fraction of RT
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Patients must have fully recovered from any prior surgery
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Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, targeted inhibitor, and/or radiotherapy with toxicities reduced to grade 1 or less (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0)
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Steroids: =< 0.5 mg/kg/day of prednisone equivalent (maximum 20 mg/day) averaged during the month prior to study enrollment is permissible
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Strong inducers or inhibitors of CYP2C8 are prohibited for 14 days before the first dose of tovorafenib (DAY101) and from planned administration for the duration of study participation
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Medications that are breast cancer resistant protein (BCRP) substrates that have a narrow therapeutic index are prohibited for 14 days before the first dose of tovorafenib (DAY101) and for the duration of study participation
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Peripheral absolute neutrophil count (ANC) >= 750/uL unless secondary to bone marrow involvement, in such cases bone marrow involvement must be documented (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment)
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Platelet count >= 75,000/uL (unsupported/without transfusion within the past 7 days) (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment)
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Patients with marrow disease must have platelet count of >= 75,000/uL (transfusion support allowed) and must not be refractory to platelet transfusions. Bone marrow involvement must be documented
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Hemoglobin >= 8 g/dL (unsupported/without transfusion within the past 7 days). Patients with marrow disease must have hemoglobin >= 8 g/dL (transfusion support allowed). Bone marrow involvement must be documented
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Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta [registered trademark]) or 7 days for short-acting growth factor
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A serum creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment)
- Age: 6 months to < 1 year; Maximum Serum Creatinine (mg/dL):= 0.5 mg/dl (male and female)
- Age: 1 to < 2 years; Maximum Serum Creatinine (mg/dL): = 0.6 mg/dl (male and female)
- Age: 2 to < 6 years; Maximum Serum Creatinine (mg/dL): = 0.8 mg/dl (male and female)
- Age: 6 to < 10 years; Maximum Serum Creatinine (mg/dL): = 1.0 mg/dl (male and female)
- Age: 10 to < 13 years; Maximum Serum Creatinine (mg/dL): = 1.2 mg/dl (male and female)
- 13 to < 16 years; Maximum Serum Creatinine (mg/dL): = 1.5 mg/dl (male) and 1.4 mg/dl (female)
- Age: >= 16 years; Maximum Serum Creatinine (mg/dL): = 1.7 mg/dl (male) and 1.4 mg/dl (female)
- OR- a 24 hour urine creatinine clearance >= 50 mL/min/1.73 m^2
- OR- a glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
- Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
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Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment)
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Alanine aminotransferase (ALT) =< 3 x ULN for age (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment)
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Serum albumin >= 2 g/dl must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment)
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For patients with liver disease caused by their histiocytic disorder (as evaluated on radiographic imaging or biopsy): patients may be enrolled with abnormal bilirubin, aspartate aminotransferase (AST), ALT and albumin with documentation of histiocytic liver disease
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Fractional shortening (FS) of >= 25% or ejection fraction of >= 50%, as determined by echocardiography or multigated acquisition scan (MUGA) within 28 days prior to study enrollment. Depending on institutional standard, either FS or left ventricular ejection fraction (LVEF) is adequate for enrollment if only one value is measured; if both values are measured, then both values must meet criteria above (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary)
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No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination; unless it is due to underlying pulmonary LCH
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Central Nervous System Function Defined As:
- Patients with seizure disorder may be enrolled if well controlled
- Central nervous system (CNS) toxicity =< Grade 2
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Human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial unless antiretroviral therapy interacts with the metabolism of tovorafenib (DAY101) and cannot safely be changed to antivirals that do not interact with study medication
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LCH arising along with other hematologic malignancy (e.g. mixed LCH with acute lymphoblastic leukemia) or any history of non-histiocytic malignancy
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Disease scenarios as below will be excluded
- Skin-limited disease
- Gastrointestinal (GI) tract involvement only (those that have disease that can be determined by endoscopic biopsies only)
- LCH-associated neurodegeneration (LCH-ND) without parenchymal lesions or other systemic lesions
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Patients with activating mutations in MAP2K1 are not eligible for this study due to drug target specificity. Mutation status will be submitted to study team within 7 days of enrollment
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Refractory nausea and vomiting, malabsorption, or external biliary shunt that would preclude adequate absorption of tovorafenib (DAY101)
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Uncontrolled systemic bacterial, viral, or fungal infection
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Major surgical procedure or significant traumatic injury within 14 days prior to study enrollment, or anticipation of need for major surgical procedure during the course of the study. Placement of a vascular access device or minor surgery is permitted within fourteen (14) days of study enrollment (provided that the wound has healed)
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History of significant bowel resection that would preclude adequate absorption or other significant malabsorptive disease
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Ophthalmologic considerations: Patients with known significant ophthalmologic conditions or known risk factors for retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible
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History of solid organ or hematopoietic bone marrow transplantation
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Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval > 440 ms based on triplicate electrocardiogram (ECG) average
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History of Grade >= 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of study entry
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History of any drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or Stevens Johnsons syndrome (SJS) or who are allergic to tovorafenib (DAY101) or any of its components
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CTCAE version (V). 5.0 Grade 3 symptomatic creatinine kinase (CPK) elevation ( > 5 x ULN)
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Female patients who are pregnant are ineligible. A pregnancy test is required for female patients of childbearing potential
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Lactating females who plan to breastfeed their infants are ineligible
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Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation are ineligible. Participants (male and female) who are sexually active must use two forms of an acceptable method of birth control (for men, one form must be a barrier method) from start of therapy through 180 days following last dose of tovorafenib (DAY101)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Treatment (tovorafenib) Biospecimen Collection Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) Bone Marrow Aspiration Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) Bone Marrow Biopsy Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) Echocardiography Test Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) Computed Tomography Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) FDG-Positron Emission Tomography and Computed Tomography Scan Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) Lumbar Puncture Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) Multigated Acquisition Scan Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. Treatment (tovorafenib) Tovorafenib Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up.
- Primary Outcome Measures
Name Time Method Frequency of dose limiting toxicity (DLT) (dose finding phase) Up to 28 days Will be analyzed descriptively.
Overall response rate (ORR) (phase II) After 2 cycles of therapy (each cycle is 28 days) Will be assessed using minimax Simon's two-stage designs in each of the BRAFV600E and non-BRAFV600E cohorts separately. The two arms will not be directly compared. The 95% confidence interval for the overall response rate will be adjusted for the two-stage design.
- Secondary Outcome Measures
Name Time Method Event free survival rate (EFS) At 1 and 2 years Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated two years after enrollment of the last patient on the trial and estimates at specific timepoints will be presented along with log-log transformed 95% confidence intervals. Events are defined as relapse/progression, second malignant neoplasm (SMN), or death.
Progression free survival rate (PFS) Up to 2 years Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated by two years after enrollment of the last patient on the trial and estimates at specific timepoints will be presented along with log-log transformed 95% confidence intervals.
Duration of response rate After 12 months of therapy. From the scan confirming the complete response or partial response (whichever is recorded first), until the first occurrence of recurrent or progressive disease or death (event) or last known status on trial Response is based on modified RECIST/PERCIST consistent with other recent pediatric LCH trials (NCT02670707 and NCT04079179) and adult histiocytosis trials with MAPK inhibitors. Comparison of response assessed via RECIST vs PERCIST will be analyzed by displaying two-way tables of the responses with no formal statistical testing.
Overall survival rate (OS) Up to 2 years Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated two years after enrollment of the last patient on the trial and estimates at specific timepoints will be presented along with log-log transformed 95% confidence intervals.
Trial Locations
- Locations (101)
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸Downey, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸Oakland, California, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸Denver, Colorado, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸Orlando, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸Atlanta, Georgia, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Blank Children's Hospital
🇺🇸Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Children's Hospital New Orleans
🇺🇸New Orleans, Louisiana, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Michigan State University Clinical Center
🇺🇸East Lansing, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸Grand Rapids, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Cardinal Glennon Children's Medical Center
🇺🇸Saint Louis, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
🇺🇸Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸Las Vegas, Nevada, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Saint Joseph's Regional Medical Center
🇺🇸Paterson, New Jersey, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
Maimonides Medical Center
🇺🇸Brooklyn, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸New Hyde Park, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
NYP/Weill Cornell Medical Center
🇺🇸New York, New York, United States
New York Medical College
🇺🇸Valhalla, New York, United States
Mission Hospital
🇺🇸Asheville, North Carolina, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸Greenville, South Carolina, United States
East Tennessee Childrens Hospital
🇺🇸Knoxville, Tennessee, United States
The Children's Hospital at TriStar Centennial
🇺🇸Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸El Paso, Texas, 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
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
Scott and White Memorial Hospital
🇺🇸Temple, Texas, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
University of Virginia Cancer Center
🇺🇸Charlottesville, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
West Virginia University Charleston Division
🇺🇸Charleston, West Virginia, United States
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Queensland Children's Hospital
🇦🇺South Brisbane, Queensland, Australia
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
Children's Hospital
🇨🇦London, Ontario, Canada
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
🇨🇦Sherbrooke, Quebec, Canada
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦Quebec, Canada