- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05828069
A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis
Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis
Study Overview
Status
Intervention / Treatment
- Procedure: Biospecimen Collection
- Procedure: Lumbar Puncture
- Procedure: Computed Tomography
- Procedure: Echocardiography
- Procedure: Multigated Acquisition Scan
- Procedure: Bone Marrow Aspiration
- Procedure: Bone Marrow Biopsy
- Drug: Tovorafenib
- Procedure: FDG-Positron Emission Tomography and Computed Tomography Scan
Detailed Description
PRIMARY OBJECTIVE:
I. To determine overall response rate (ORR) for children and young adults with relapsed or refractory 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 and then every 3, 6, 9, and 12 months.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Ontario
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Toronto, Ontario, Canada, M5G 1X8
- Recruiting
- Hospital for Sick Children
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Contact:
- Site Public Contact
- Phone Number: 416-813-7654
- Email: ask.CRS@sickkids.ca
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Principal Investigator:
- Oussama A. Abla
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-
-
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Alabama
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Birmingham, Alabama, United States, 35233
- Suspended
- Children's Hospital of Alabama
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California
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Downey, California, United States, 90242
- Recruiting
- Kaiser Permanente Downey Medical Center
-
Contact:
- Site Public Contact
- Phone Number: 626-564-3455
-
Principal Investigator:
- Robert M. Cooper
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Loma Linda, California, United States, 92354
- Recruiting
- Loma Linda University Medical Center
-
Contact:
- Site Public Contact
- Phone Number: 909-558-4050
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Principal Investigator:
- Albert Kheradpour
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Los Angeles, California, United States, 90027
- Recruiting
- Children's Hospital Los Angeles
-
Contact:
- Site Public Contact
- Phone Number: 323-361-4110
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Principal Investigator:
- Rebecca S. Parker
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Madera, California, United States, 93636
- Recruiting
- Valley Children's Hospital
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Contact:
- Site Public Contact
- Phone Number: 559-353-3000
- Email: Research@valleychildrens.org
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Principal Investigator:
- Karen S. Fernandez
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Oakland, California, United States, 94611
- Recruiting
- Kaiser Permanente-Oakland
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Contact:
- Site Public Contact
- Phone Number: 877-642-4691
- Email: Kpoct@kp.org
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Principal Investigator:
- Aarati V. Rao
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Oakland, California, United States, 94609
- Recruiting
- UCSF Benioff Children's Hospital Oakland
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Principal Investigator:
- Jennifer G. Michlitsch
-
Contact:
- Site Public Contact
- Phone Number: 510-428-3264
- Email: cogbchoak@ucsf.edu
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Orange, California, United States, 92868
- Recruiting
- Children's Hospital of Orange County
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Contact:
- Site Public Contact
- Phone Number: 714-509-8646
- Email: oncresearch@choc.org
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Principal Investigator:
- Elyssa M. Rubin
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San Francisco, California, United States, 94158
- Recruiting
- UCSF Medical Center-Mission Bay
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Contact:
- Site Public Contact
- Phone Number: 877-827-3222
- Email: cancertrials@ucsf.edu
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Principal Investigator:
- Michelle L. Hermiston
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Colorado
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Denver, Colorado, United States, 80218
- Recruiting
- Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
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Contact:
- Site Public Contact
- Phone Number: 303-839-6000
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Principal Investigator:
- Jennifer J. Clark
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Connecticut
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Hartford, Connecticut, United States, 06106
- Recruiting
- Connecticut Children's Medical Center
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Contact:
- Site Public Contact
- Phone Number: 860-545-9981
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Principal Investigator:
- Michael S. Isakoff
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Delaware
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Wilmington, Delaware, United States, 19803
- Recruiting
- Alfred I duPont Hospital for Children
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Contact:
- Site Public Contact
- Phone Number: 302-651-5572
- Email: Allison.bruce@nemours.org
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Principal Investigator:
- Ramamoorthy Nagasubramanian
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Florida
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Fort Myers, Florida, United States, 33908
- Recruiting
- Golisano Children's Hospital of Southwest Florida
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Contact:
- Site Public Contact
- Phone Number: 239-343-5333
- Email: molly.arnstrom@leehealth.org
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Principal Investigator:
- Emad K. Salman
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Gainesville, Florida, United States, 32610
- Recruiting
- University of Florida Health Science Center - Gainesville
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Contact:
- Site Public Contact
- Phone Number: 352-273-8010
- Email: cancer-center@ufl.edu
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Principal Investigator:
- William B. Slayton
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Jacksonville, Florida, United States, 32207
- Recruiting
- Nemours Children's Clinic-Jacksonville
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Contact:
- Site Public Contact
- Phone Number: 302-651-5572
- Email: Allison.bruce@nemours.org
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Principal Investigator:
- Ramamoorthy Nagasubramanian
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Miami, Florida, United States, 33155
- Recruiting
- Nicklaus Children's Hospital
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Contact:
- Site Public Contact
- Phone Number: 888-624-2778
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Principal Investigator:
- Maggie E. Fader
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Tampa, Florida, United States, 33607
- Recruiting
- Saint Joseph's Hospital/Children's Hospital-Tampa
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Contact:
- Site Public Contact
- Phone Number: 813-357-0849
- Email: jennifer.manns@baycare.org
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Principal Investigator:
- Don E. Eslin
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Illinois
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Chicago, Illinois, United States, 60637
- Recruiting
- University of Chicago Comprehensive Cancer Center
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Contact:
- Site Public Contact
- Phone Number: 773-702-8222
- Email: cancerclinicaltrials@bsd.uchicago.edu
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Principal Investigator:
- Lindsay F. Schwartz
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Indiana
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Indianapolis, Indiana, United States, 46202
- Recruiting
- Riley Hospital for Children
-
Contact:
- Site Public Contact
- Phone Number: 800-248-1199
-
Principal Investigator:
- Anthony Ross
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Iowa
-
Iowa City, Iowa, United States, 52242
- Recruiting
- University of Iowa/Holden Comprehensive Cancer Center
-
Contact:
- Site Public Contact
- Phone Number: 800-237-1225
-
Principal Investigator:
- David S. Dickens
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Kentucky
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Lexington, Kentucky, United States, 40536
- Recruiting
- University of Kentucky/Markey Cancer Center
-
Contact:
- Site Public Contact
- Phone Number: 859-257-3379
-
Principal Investigator:
- James T. Badgett
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Louisiana
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New Orleans, Louisiana, United States, 70118
- Recruiting
- Children's Hospital New Orleans
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Contact:
- Site Public Contact
- Email: CHResearch@lcmchealth.org
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Principal Investigator:
- Lolie C. Yu
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Michigan
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East Lansing, Michigan, United States, 48824
- Recruiting
- Michigan State University Clinical Center
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Contact:
- Site Public Contact
- Phone Number: 517-975-9547
-
Principal Investigator:
- Laura E. Agresta
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Grand Rapids, Michigan, United States, 49503
- Recruiting
- Helen DeVos Children's Hospital at Spectrum Health
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Principal Investigator:
- Kathleen J. Yost
-
Contact:
- Site Public Contact
- Phone Number: 616-267-1925
- Email: crcwm-regulatory@crcwm.org
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Minnesota
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Minneapolis, Minnesota, United States, 55404
- Recruiting
- Children's Hospitals and Clinics of Minnesota - Minneapolis
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Principal Investigator:
- Michael K. Richards
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Contact:
- Site Public Contact
- Phone Number: 612-813-5913
- Email: pauline.mitby@childrensmn.org
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Minneapolis, Minnesota, United States, 55455
- Recruiting
- University of Minnesota/Masonic Cancer Center
-
Contact:
- Site Public Contact
- Phone Number: 612-624-2620
-
Principal Investigator:
- Lucie M. Turcotte
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Mississippi
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Jackson, Mississippi, United States, 39216
- Recruiting
- University of Mississippi Medical Center
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Principal Investigator:
- Betty L. Herrington
-
Contact:
- Site Public Contact
- Phone Number: 601-815-6700
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Missouri
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Saint Louis, Missouri, United States, 63110
- Recruiting
- Washington University School of Medicine
-
Contact:
- Site Public Contact
- Phone Number: 800-600-3606
- Email: info@siteman.wustl.edu
-
Principal Investigator:
- Bryan A. Sisk
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Saint Louis, Missouri, United States, 63141
- Recruiting
- Mercy Hospital Saint Louis
-
Contact:
- Site Public Contact
- Phone Number: 314-251-7066
-
Principal Investigator:
- Robin D. Hanson
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Nevada
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Las Vegas, Nevada, United States, 89135
- Recruiting
- Alliance for Childhood Diseases/Cure 4 the Kids Foundation
-
Contact:
- Site Public Contact
- Phone Number: 702-384-0013
- Email: research@sncrf.org
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Principal Investigator:
- Alan K. Ikeda
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Las Vegas, Nevada, United States, 89144
- Recruiting
- Summerlin Hospital Medical Center
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Contact:
- Site Public Contact
- Phone Number: 702-384-0013
- Email: research@sncrf.org
-
Principal Investigator:
- Alan K. Ikeda
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New Jersey
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Hackensack, New Jersey, United States, 07601
- Recruiting
- Hackensack University Medical Center
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Contact:
- Site Public Contact
- Phone Number: 201-996-2879
-
Principal Investigator:
- Katharine Offer
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Paterson, New Jersey, United States, 07503
- Recruiting
- Saint Joseph's Regional Medical Center
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Contact:
- Site Public Contact
- Phone Number: 973-754-2207
- Email: HallL@sjhmc.org
-
Principal Investigator:
- Alissa Kahn
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New York
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Albany, New York, United States, 12208
- Recruiting
- Albany Medical Center
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Contact:
- Site Public Contact
- Phone Number: 518-262-5513
-
Principal Investigator:
- Lauren R. Weintraub
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Bronx, New York, United States, 10467
- Recruiting
- Montefiore Medical Center - Moses Campus
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Contact:
- Site Public Contact
- Phone Number: 718-379-6866
- Email: eskwak@montefiore.org
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Principal Investigator:
- Alice Lee
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Brooklyn, New York, United States, 11219
- Recruiting
- Maimonides Medical Center
-
Contact:
- Site Public Contact
- Phone Number: 718-765-2500
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Principal Investigator:
- Mahmut Y. Celiker
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New Hyde Park, New York, United States, 11040
- Recruiting
- The Steven and Alexandra Cohen Children's Medical Center of New York
-
Contact:
- Site Public Contact
- Phone Number: 718-470-3460
-
Principal Investigator:
- Julie I. Krystal
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New York, New York, United States, 10065
- Recruiting
- NYP/Weill Cornell Medical Center
-
Contact:
- Site Public Contact
- Phone Number: 212-746-1848
-
Principal Investigator:
- Nitya Gulati
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Valhalla, New York, United States, 10595
- Recruiting
- New York Medical College
-
Contact:
- Site Public Contact
- Phone Number: 914-594-3794
-
Principal Investigator:
- Jessica C. Hochberg
-
-
North Carolina
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Greenville, North Carolina, United States, 27834
- Recruiting
- East Carolina University
-
Contact:
- Site Public Contact
- Phone Number: 252-744-1015
- Email: eubankss@ecu.edu
-
Principal Investigator:
- Andrea R. Whitfield
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Winston-Salem, North Carolina, United States, 27157
- Recruiting
- Wake Forest University Health Sciences
-
Contact:
- Site Public Contact
- Phone Number: 336-713-6771
-
Principal Investigator:
- Thomas W. McLean
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Ohio
-
Cleveland, Ohio, United States, 44106
- Recruiting
- Rainbow Babies and Childrens Hospital
-
Contact:
- Site Public Contact
- Phone Number: 216-844-5437
-
Principal Investigator:
- Duncan S. Stearns
-
Columbus, Ohio, United States, 43205
- Recruiting
- Nationwide Children's Hospital
-
Contact:
- Site Public Contact
- Phone Number: 614-722-6039
- Email: Melinda.Triplet@nationwidechildrens.org
-
Principal Investigator:
- Mark A. Ranalli
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Dayton, Ohio, United States, 45404
- Recruiting
- Dayton Children's Hospital
-
Contact:
- Site Public Contact
- Phone Number: 800-228-4055
-
Principal Investigator:
- Mukund G. Dole
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-
Oklahoma
-
Oklahoma City, Oklahoma, United States, 73104
- Recruiting
- University of Oklahoma Health Sciences Center
-
Contact:
- Site Public Contact
- Phone Number: 405-271-8777
- Email: ou-clinical-trials@ouhsc.edu
-
Principal Investigator:
- Rene Y. McNall-Knapp
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Oregon
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Portland, Oregon, United States, 97239
- Recruiting
- Oregon Health and Science University
-
Contact:
- Site Public Contact
- Phone Number: 503-494-1080
- Email: trials@ohsu.edu
-
Principal Investigator:
- Katrina Winsnes
-
-
Pennsylvania
-
Philadelphia, Pennsylvania, United States, 19104
- Recruiting
- Children's Hospital of Philadelphia
-
Principal Investigator:
- Michael D. Hogarty
-
Contact:
- Site Public Contact
- Phone Number: 267-425-5544
- Email: CancerTrials@email.chop.edu
-
Philadelphia, Pennsylvania, United States, 19134
- Recruiting
- Saint Christopher's Hospital for Children
-
Contact:
- Site Public Contact
- Phone Number: 215-427-8991
-
Principal Investigator:
- Gregory E. Halligan
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Pittsburgh, Pennsylvania, United States, 15224
- Recruiting
- Children's Hospital of Pittsburgh of UPMC
-
Contact:
- Site Public Contact
- Phone Number: 412-692-8570
- Email: jean.tersak@chp.edu
-
Principal Investigator:
- Andrew Bukowinski
-
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South Carolina
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Columbia, South Carolina, United States, 29203
- Recruiting
- Prisma Health Richland Hospital
-
Contact:
- Site Public Contact
- Phone Number: 864-241-6251
-
Principal Investigator:
- Stuart L. Cramer
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Greenville, South Carolina, United States, 29605
- Recruiting
- BI-LO Charities Children's Cancer Center
-
Contact:
- Site Public Contact
- Phone Number: 864-241-6251
-
Principal Investigator:
- Aniket Saha
-
-
Tennessee
-
Nashville, Tennessee, United States, 37203
- Recruiting
- The Children's Hospital at TriStar Centennial
-
Contact:
- Site Public Contact
- Phone Number: 615-342-1919
-
Principal Investigator:
- Jennifer A. Domm
-
-
Texas
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Austin, Texas, United States, 78723
- Recruiting
- Dell Children's Medical Center of Central Texas
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Contact:
- Site Public Contact
- Phone Number: 512-628-1902
- Email: TXAUS-DL-SFCHemonc.research@ascension.org
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Principal Investigator:
- Shannon M. Cohn
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Houston, Texas, United States, 77030
- Recruiting
- M D Anderson Cancer Center
-
Contact:
- Site Public Contact
- Phone Number: 877-632-6789
- Email: askmdanderson@mdanderson.org
-
Principal Investigator:
- Najat C. Daw
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Houston, Texas, United States, 77030
- Recruiting
- Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
-
Contact:
- Site Public Contact
- Phone Number: 713-798-1354
- Email: burton@bcm.edu
-
Principal Investigator:
- Olive S. Eckstein
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San Antonio, Texas, United States, 78207
- Recruiting
- Children's Hospital of San Antonio
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Contact:
- Site Public Contact
- Phone Number: 210-704-2894
- Email: bridget.medina@christushealth.org
-
Principal Investigator:
- Timothy C. Griffin
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San Antonio, Texas, United States, 78229
- Recruiting
- University of Texas Health Science Center at San Antonio
-
Contact:
- Site Public Contact
- Phone Number: 210-450-3800
- Email: phoresearchoffice@uthscsa.edu
-
Principal Investigator:
- Anne-Marie R. Langevin
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Temple, Texas, United States, 76508
- Recruiting
- Scott and White Memorial Hospital
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Contact:
- Site Public Contact
- Phone Number: 254-724-5407
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Principal Investigator:
- Nicholas W. McGregor
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Utah
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Salt Lake City, Utah, United States, 84113
- Recruiting
- Primary Children's Hospital
-
Contact:
- Site Public Contact
- Phone Number: 801-585-5270
-
Principal Investigator:
- Taumoha Ghosh
-
-
Virginia
-
Charlottesville, Virginia, United States, 22908
- Recruiting
- University of Virginia Cancer Center
-
Contact:
- Site Public Contact
- Phone Number: 434-243-6303
- Email: uvacancertrials@hscmail.mcc.virginia.edu
-
Principal Investigator:
- Brian C. Belyea
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Norfolk, Virginia, United States, 23507
- Recruiting
- Children's Hospital of The King's Daughters
-
Contact:
- Site Public Contact
- Phone Number: 757-668-7243
- Email: CCBDCresearch@chkd.org
-
Principal Investigator:
- Eric J. Lowe
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Richmond, Virginia, United States, 23298
- Recruiting
- Virginia Commonwealth University/Massey Cancer Center
-
Contact:
- Site Public Contact
- Email: CTOclinops@vcu.edu
-
Principal Investigator:
- Nadirah El-Amin
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Washington
-
Seattle, Washington, United States, 98105
- Recruiting
- Seattle Children's Hospital
-
Contact:
- Site Public Contact
- Phone Number: 866-987-2000
-
Principal Investigator:
- Sarah E. Leary
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Spokane, Washington, United States, 99204
- Recruiting
- Providence Sacred Heart Medical Center and Children's Hospital
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Contact:
- Site Public Contact
- Phone Number: 800-228-6618
- Email: HopeBeginsHere@providence.org
-
Principal Investigator:
- Judy L. Felgenhauer
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 180 days- < 22 years (at time of study enrollment)
Patients with multifocal progressive, relapsed, or recurrent LCH with measurable disease at study entry
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
- 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 chemotherapy treatment strategy
- 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
- 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
- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50% for patients =< 16 years of age
- 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
- Myelosuppressive chemotherapy: Patients must not have received within 14 days of entry onto this study
- Investigational agent or any other anticancer therapy not defined above: Patients must not have received any investigational agent for at least 14 days prior to planned start of tovorafenib (DAY101)
- Radiation therapy (RT): Patient must not have received RT within 2 weeks after the last dose fraction of RT
- Patients must have fully recovered from any prior surgery
- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy with toxicities reduced to Grade 1 or less (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0)
- Steroids: < 0.5 mg/kg/day of prednisone equivalent (maximum 20 mg/day) averaged during the month prior to study enrollment is permissible but must be discontinued fourteen (14) days prior to study enrollment. Patients with documented brain lesions receiving corticosteroids for management of cerebral edema must be on a stable dose for fourteen (14) days prior to study enrollment
- 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
- 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
- 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)
- 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)
- 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
- 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
- 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
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
- 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)
- 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)
- 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)
- 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
- 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)
- 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
Central Nervous System Function Defined As:
- Patients with seizure disorder may be enrolled if well controlled
- Central nervous system (CNS) toxicity =< Grade 2
- 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
Exclusion Criteria:
- LCH arising along with other hematologic malignancy (e.g. mixed LCH with acute lymphoblastic leukemia) or any history of non-histiocytic malignancy
Disease scenarios as below will be excluded
- Skin-limited disease
- Single bone lesion
- 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
- 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
- Patient must not have received any prior MAPK pathway inhibitor therapy
- Refractory nausea and vomiting, malabsorption, or external biliary shunt that would preclude adequate absorption of tovorafenib (DAY101)
- Uncontrolled systemic bacterial, viral, or fungal infection
- 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)
- History of significant bowel resection that would preclude adequate absorption or other significant malabsorptive disease
- 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
- History of solid organ or hematopoietic bone marrow transplantation
- 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
- History of Grade >= 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of study entry
- 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
- CTCAE version (V). 5.0 Grade 3 symptomatic creatinine kinase (CPK) elevation ( > 5 x ULN)
- Female patients who are pregnant are ineligible. A pregnancy test is required for female patients of childbearing potential
- Lactating females who plan to breastfeed their infants are ineligible
- 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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (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.
|
Undergo collection of blood samples
Other Names:
Undergo lumbar puncture
Other Names:
Undergo CT
Other Names:
Undergo ECHO
Other Names:
Undergo MUGA
Other Names:
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Other Names:
Given PO
Other Names:
Undergo FDG-PET imaging
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Frequency of dose limiting toxicity (DLT) (dose finding phase)
Time Frame: Up to 28 days
|
Will be analyzed descriptively.
|
Up to 28 days
|
Overall response rate (ORR) (phase II)
Time Frame: After 2 cycles of therapy (each cycle is 28 days)
|
The 95% confidence interval for the overall response rate will be adjusted for the two-stage design.
|
After 2 cycles of therapy (each cycle is 28 days)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Event free survival rate (EFS)
Time Frame: At 1 and 2 years
|
Will be estimated by the Kaplan-Meier method beginning at study enrollment.
Will be evaluated using the Log-rank test 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.
|
At 1 and 2 years
|
Progression free survival rate (PFS)
Time Frame: Up to 2 years
|
Will be estimated by the Kaplan-Meier method beginning at study enrollment.
Will be evaluated by using the Log-rank test 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.
|
Up to 2 years
|
Duration of response rate
Time Frame: 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.
|
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
|
Overall survival rate (OS)
Time Frame: Up to 2 years
|
Will be estimated by the Kaplan-Meier method beginning at study enrollment.
Will be evaluated using the Log-rank test 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.
|
Up to 2 years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percent peripheral blood mononuclear cells (PBMC) with mutated allele
Time Frame: Up to 2 years
|
Will be analyzed descriptively using logistic regression with complete response (CR)/progressive response (PR) vs. stable disease (SD)/progressive disease (PD) as the response variable
|
Up to 2 years
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Michelle L Hermiston, Children's Oncology Group
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NCI-2022-06282 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- U10CA180886 (U.S. NIH Grant/Contract)
- ANHL2121 (Other Identifier: CTEP)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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