Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial

Phase 2

Active, not recruiting

• Conditions: Malignant Solid Neoplasm; Recurrent Ependymoma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Rhabdoid Tumor; Recurrent Rhabdoid Tumor of the Kidney; Recurrent Adrenal Gland Pheochromocytoma; Recurrent Malignant Glioma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma
• Interventions: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration and Biopsy; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography; Procedure: Radionuclide Imaging; Drug: Tipifarnib

• Registration Number: NCT04284774
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II pediatric MATCH trial studies how well tipifarnib works in treating patients with solid tumors that have recurred or spread to other places in the body (advanced), lymphoma, or histiocytic disorders, that have a genetic alteration in the gene HRAS. Tipifarnib may block the growth of cancer cells that have specific genetic changes in a gene called HRAS and may reduce tumor size.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with tipifarnib with advanced solid tumors (including central nervous system \[CNS\] tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in HRAS.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with tipifarnib with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in HRAS.

II. To obtain information about the tolerability of tipifarnib in children and adolescents with relapsed or refractory cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate other biomarkers as predictors of response to tipifarnib and specifically, whether tumors that harbor different missense mutations or variant allele frequency will demonstrate differential response to tipifarnib treatment.

II. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).

OUTLINE:

Patients receive tipifarnib orally (PO) or via nasogastric or gastric tube twice daily (BID) on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with positron emission tomography (PET) scan, computed tomography (CT) scan, magnetic resonance imaging (MRI), or meta-iodobenzylguanidine (MIBG) scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.

After completion of study treatment, patients are followed up at 30 days, then periodically thereafter.

Study Timeline

• Study First Submitted: 2020-02-25
• Study First Submitted QC: 2020-02-25
• Study First Posted: 2020-02-26
• Study Start: 2020-10-13
• Primary Completion: 2024-03-31
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-16
• Last Update Posted: 2024-10-17
• Study Completion: 2025-04-16

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 5

Inclusion Criteria

• Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621M based on the presence of an actionable mutation as defined in APEC1621SC

• Patients must be >=12 months and =< 21 years of age at the time of study enrollment

• Patients must have a body surface area >= 0.29 m^2 at enrollment

• Patients must have radiographically measurable disease at the time of study enrollment. Patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable disease are eligible. Measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)

  • 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 cerebral spinal 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 relatively 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 radio-pharmaceutical therapy

  • Patients must not have received prior exposure to tipifarnib

• For patients with solid tumors without known bone marrow involvement (within 7 days prior to enrollment):

  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

• For patients with solid tumors without known bone marrow involvement (within 7 days prior to enrollment):

  • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

• 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 (within 7 days prior to enrollment) or

• A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

  • Age: Maximum serum creatinine (mg/dL)

    • 1 to < 2 years: male (0.6), female (0.6)
    • 2 to < 6 years: male (0.8), female (0.8)
    • 6 to < 10 years: male (1), female (1)
    • 10 to < 13 years: male (1.2), female (1.2)
    • 13 to < 16 years: male (1.5), female (1.4)
    • >= 16 years: male (1.7), female (1.4)

• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)

• 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.) (within 7 days prior to enrollment)

• Serum albumin >= 2 g/dL (within 7 days prior to enrollment)

• 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] 5.0) resulting from prior therapy must be =< grade 2

• Patients must be able to swallow intact tablets or crushed tablets mixed in water, orange juice, apple juice, tomato juice, ginger ale, applesauce, yogurt, protein shake, or a dietary supplement drink (such as Ensure). Percutaneous endoscopic gastrostomy (PEG)-tube or nasogastric tube administration is permitted

• 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 due to risks of fetal and teratogenic adverse events as seen in animal/human studies. 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 two effective contraceptive methods for the duration of study treatment. Both female subjects and male subjects with female partners of child-bearing potential must agree to use a highly effective method of contraception for 2 weeks prior to protocol therapy, during, and at least 4 weeks after last dose of tipifarnib. In addition, since tipifarnib could induce toxicity of male reproductive organs and cause impairment of fertility, sperm cryopreservation should be recommended for male subjects wishing to preserve their fertility following tipifarnib treatment
• 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 inhibitors of CYP3A4/5 or UGT are not eligible. Strong inducers or inhibitors of CYP3A4/5 or UGT should be avoided from 14 days prior to the 1st dose of tipifarnib to the end of the study. In addition, patients receiving agents that are sensitive or narrow therapeutic range substrates of CYP3A4/5 are not eligible. Note: CYP3A4/5 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed
• Patients with known hypersensitivity to tipifarnib or any components of the tablet are not eligible
• Patients with hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (tipifarnib)	Biospecimen Collection	Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
Treatment (tipifarnib)	Bone Marrow Aspiration and Biopsy	Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
Treatment (tipifarnib)	Computed Tomography	Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
Treatment (tipifarnib)	Magnetic Resonance Imaging	Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
Treatment (tipifarnib)	Positron Emission Tomography	Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
Treatment (tipifarnib)	Radionuclide Imaging	Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
Treatment (tipifarnib)	Tipifarnib	Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.

Primary Outcome Measures

Name	Time	Method
Objective response rate (complete response + partial response) in pediatric patients treated with tipifarnib	From enrollment to the end of treatment, up to 2 years	A responder is defined as a patient who achieves a best response of partial response or complete response on the study. Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method. The revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to determine response and progression in this study, with specific criteria outlined for the different subtypes of tumors (e.g., 2-dimensional measurements for central nervous system (CNS) tumors.

Secondary Outcome Measures

Name	Time	Method
Percentage of patients experiencing grade 3 or higher adverse events	From enrollment to the end of treatment, up to 2 years	Percentage of patients experiencing grade 3 or higher adverse events will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All patients who receive at least one dose of protocol therapy will be considered in the evaluation of toxicity.
Progression free survival (PFS)	At 6 months	PFS is defined as time from the initiation of subprotocol treatment, until disease progression, recurrence, death from any cause or date of last contact.

Trial Locations

Locations (172)

Children's Healthcare of Atlanta - Arthur M Blank Hospital; 🇺🇸 Atlanta, Georgia, United States

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

Providence Alaska Medical Center; 🇺🇸 Anchorage, Alaska, United States

Banner Children's at Desert; 🇺🇸 Mesa, Arizona, United States

Phoenix Childrens Hospital; 🇺🇸 Phoenix, Arizona, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center; 🇺🇸 Downey, California, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, 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

Cedars Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Mattel Children's Hospital UCLA; 🇺🇸 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

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Rady Children's Hospital - San Diego; 🇺🇸 San Diego, California, United States

Naval Medical Center -San Diego; 🇺🇸 San Diego, California, United States

UCSF Medical Center-Mission Bay; 🇺🇸 San Francisco, California, United States

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center; 🇺🇸 Torrance, 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

MedStar Georgetown University Hospital; 🇺🇸 Washington, District of Columbia, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Broward Health Medical Center; 🇺🇸 Fort Lauderdale, Florida, 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

Memorial Regional Hospital/Joe DiMaggio Children's Hospital; 🇺🇸 Hollywood, Florida, United States

Nemours Children's Clinic-Jacksonville; 🇺🇸 Jacksonville, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center; 🇺🇸 Miami, Florida, United States

Nicklaus Children's Hospital; 🇺🇸 Miami, Florida, United States

Miami Cancer Institute; 🇺🇸 Miami, Florida, 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

Sacred Heart Hospital; 🇺🇸 Pensacola, Florida, United States

Johns Hopkins All Children's Hospital; 🇺🇸 Saint Petersburg, Florida, United States

Tampa General Hospital; 🇺🇸 Tampa, Florida, United States

Saint Joseph's Hospital/Children's Hospital-Tampa; 🇺🇸 Tampa, Florida, United States

Saint Mary's Hospital; 🇺🇸 West Palm Beach, Florida, United States

Memorial Health University Medical Center; 🇺🇸 Savannah, Georgia, United States

Kapiolani Medical Center for Women and Children; 🇺🇸 Honolulu, Hawaii, United States

Saint Luke's Cancer Institute - Boise; 🇺🇸 Boise, Idaho, United States

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

University of Illinois; 🇺🇸 Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

Saint Jude Midwest Affiliate; 🇺🇸 Peoria, Illinois, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Riley Hospital for Children; 🇺🇸 Indianapolis, Indiana, United States

Ascension Saint Vincent Indianapolis Hospital; 🇺🇸 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

Norton Children's Hospital; 🇺🇸 Louisville, Kentucky, United States

Children's Hospital New Orleans; 🇺🇸 New Orleans, Louisiana, United States

Ochsner Medical Center Jefferson; 🇺🇸 New Orleans, Louisiana, United States

Eastern Maine Medical Center; 🇺🇸 Bangor, Maine, United States

Maine Children's Cancer Program; 🇺🇸 Scarborough, Maine, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Sinai Hospital of Baltimore; 🇺🇸 Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

UMass Memorial Medical Center - University Campus; 🇺🇸 Worcester, Massachusetts, United States

C S Mott Children's Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Children's Hospital of Michigan; 🇺🇸 Detroit, Michigan, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, 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

Bronson Methodist Hospital; 🇺🇸 Kalamazoo, Michigan, United States

Corewell Health Children's; 🇺🇸 Royal Oak, 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

Children's Mercy Hospitals and Clinics; 🇺🇸 Kansas City, Missouri, 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

University Medical Center of Southern Nevada; 🇺🇸 Las Vegas, Nevada, United States

Sunrise Hospital and Medical Center; 🇺🇸 Las Vegas, Nevada, 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

Renown Regional Medical Center; 🇺🇸 Reno, Nevada, United States

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center; 🇺🇸 Lebanon, New Hampshire, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Saint Peter's University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Albany Medical Center; 🇺🇸 Albany, New York, United States

Montefiore Medical Center - Moses Campus; 🇺🇸 Bronx, New York, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

NYU Langone Hospital - Long Island; 🇺🇸 Mineola, New York, United States

The Steven and Alexandra Cohen Children's Medical Center of New York; 🇺🇸 New Hyde Park, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone; 🇺🇸 New York, 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

University of Rochester; 🇺🇸 Rochester, New York, United States

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

State University of New York Upstate Medical University; 🇺🇸 Syracuse, New York, United States

New York Medical College; 🇺🇸 Valhalla, New York, United States

Mission Hospital; 🇺🇸 Asheville, North Carolina, United States

UNC Lineberger Comprehensive Cancer Center; 🇺🇸 Chapel Hill, North Carolina, United States

Carolinas Medical Center/Levine Cancer Institute; 🇺🇸 Charlotte, North Carolina, United States

Novant Health Presbyterian Medical Center; 🇺🇸 Charlotte, North Carolina, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

East Carolina University; 🇺🇸 Greenville, North Carolina, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

Sanford Broadway Medical Center; 🇺🇸 Fargo, North Dakota, United States

Children's Hospital Medical Center of Akron; 🇺🇸 Akron, Ohio, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital; 🇺🇸 Cleveland, Ohio, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Dayton Children's Hospital; 🇺🇸 Dayton, Ohio, United States

ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital; 🇺🇸 Toledo, Ohio, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Legacy Emanuel Children's Hospital; 🇺🇸 Portland, Oregon, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Lehigh Valley Hospital-Cedar Crest; 🇺🇸 Allentown, Pennsylvania, 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

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States

Prisma Health Richland Hospital; 🇺🇸 Columbia, South Carolina, United States

BI-LO Charities Children's Cancer Center; 🇺🇸 Greenville, South Carolina, United States

Sanford USD Medical Center - Sioux Falls; 🇺🇸 Sioux Falls, South Dakota, United States

T C Thompson Children's Hospital; 🇺🇸 Chattanooga, Tennessee, United States

East Tennessee Childrens Hospital; 🇺🇸 Knoxville, Tennessee, United States

Saint Jude Children's Research Hospital; 🇺🇸 Memphis, 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

Driscoll Children's Hospital; 🇺🇸 Corpus Christi, Texas, United States

Medical City Dallas Hospital; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

El Paso Children's Hospital; 🇺🇸 El Paso, Texas, United States

Cook Children's Medical Center; 🇺🇸 Fort Worth, 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

Covenant Children's Hospital; 🇺🇸 Lubbock, Texas, United States

UMC Cancer Center / UMC Health System; 🇺🇸 Lubbock, 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

Scott and White Memorial Hospital; 🇺🇸 Temple, Texas, United States

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States

University of Vermont and State Agricultural College; 🇺🇸 Burlington, Vermont, United States

Inova Fairfax Hospital; 🇺🇸 Falls Church, Virginia, United States

Children's Hospital of The King's Daughters; 🇺🇸 Norfolk, Virginia, United States

Naval Medical Center - Portsmouth; 🇺🇸 Portsmouth, 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

Mary Bridge Children's Hospital and Health Center; 🇺🇸 Tacoma, Washington, United States

Madigan Army Medical Center; 🇺🇸 Tacoma, Washington, United States

West Virginia University Healthcare; 🇺🇸 Morgantown, West Virginia, United States

University of Wisconsin Carbone Cancer Center - University Hospital; 🇺🇸 Madison, Wisconsin, United States

Marshfield Medical Center-Marshfield; 🇺🇸 Marshfield, Wisconsin, United States

Children's Hospital of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

University Pediatric Hospital; 🇵🇷 San Juan, Puerto Rico