Tovorafenib for Treatment of Craniopharyngioma in Children and Young Adults

NCT05465174 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 210828NCI-2022-05356
• Study Type: interventional
• Target: 57
• Locations: 2 countries
• Sites: 20

Brief Summary

The current study assesses the tolerability and efficacy of monotherapy with pan-RAF-kinase (Tovorafenib) inhibition for the treatment of children and young adults with craniopharyngioma.

Conditions

Craniopharyngioma, Child; Craniopharyngioma; Recurrent Craniopharyngioma

Keywords

Neoadjuvant therapy

Outcome Measures

Primary Outcomes (2)

• Progression free survival rate (PFS)

  Progression-free survival is defined as the time of documented response until disease progression as defined by Response assessment in neuro-oncology criteria (RANO) criteria. PFS will be reported by overall group at 12 months.

  Up to 12 months

• Changes in scores on the Physical functioning subscale of the Pediatric Quality of Life Inventory (PedsQL) over time

  Scores over time from the PedsQL 4.0 Generic Core physical function domain rating form, which have multidimensional child self-report and parent proxy report scales to assess health-related quality of life (QOL) in children, adolescents, and young adults ages 2 - 25 years will be reported. Physical functioning, is the sub-scale of interest for this protocol. Items on the physical functioning sub-scale are scored on a 5-point Likert scale with raw scores ranging from 0- 4. Items are reversed scored and linearly transformed to a 0-100 scale. If more than 50% of the items in the scale are missing, the Scale Scores should not be computed. Higher scores indicate a higher level of physical functioning

  Up to 12 months

Secondary Outcomes (2)

• Proportion of participants with visual deficits over time

  Up to 5 years

• Proportion of participants with neuroendocrine deficits

  Up to 5 years

Study Arms (3)

Group 1: Neoadjuvant Tovorafenib

EXPERIMENTAL

Participants with newly diagnosed craniopharyngioma will receive one (1) dose of Tovorafenib within 7 days +/- 2 days prior to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or sub-total (STR) or near-total resection (NTR) will continue on maintenance monotherapy of Tovorafenib given once weekly at the respected recommended phase 2 dose (RP2D). Participants having undergone a gross total resection (GTR) will enter into follow-up only and will be part of the exploratory cohort.

Drug: Tovorafenib

Group 2, Arm A: Neoadjuvant Tovorafenib

EXPERIMENTAL

Participants with recurrent craniopharyngioma will receive one (1) dose of Tovorafenib within 7 days +/- 2 days prior to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or STR or NTR will continue on maintenance monotherapy of Tovorafenib given once weekly at the respected RP2D.

Drug: Tovorafenib

Group 2, Arm B: Non-biopsy/resection participants

EXPERIMENTAL

Non-biopsy/resection participants with recurrent disease will receive monotherapy of Tovorafenib given once weekly at the respected RP2D.

Drug: Tovorafenib

Interventions

Tovorafenib DRUG

Given orally

Also known as: DAY101, TAK580, AMG-2112819, BSK1369

Group 1: Neoadjuvant Tovorafenib; Group 2, Arm A: Neoadjuvant Tovorafenib; Group 2, Arm B: Non-biopsy/resection participants

Eligibility Criteria

• Age: 1 Year - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Newly Diagnosed Participants:
• Newly diagnosed craniopharyngioma, as based on imaging characteristics and central radiology review. Participants will initially be screened within confines of a screening consent and only those participants with findings consistent with craniopharyngioma and without findings suggesting an indeterminate lesion or lesion of an alternative diagnosis (including abnormal tumor markers found in blood or cerebral spinal fluid (CSF), if completed as part of standard of care (SOC) work-up or if lesion concerning for alternate diagnosis) will move ahead with enrollment on the treatment protocol. Additionally, for participants that have undergone initial biopsy to confirm diagnosis, are within 6 weeks of radiographic diagnosis, and are planned to undergo follow up second surgery for additional tumor resection as per standard of care recommendations, these participants will also be considered eligible.
• Participants must be surgical candidates for biopsy or resection and planned for standard of care biopsy or resection.
• Recurrent Participants:
• Recurrent craniopharyngioma, as based on histologic confirmation at time of initial diagnosis (participants with Adamantinomatous craniopharyngioma (ACP) will only be eligible for the recurrent arm).
• Recurrent craniopharyngioma without prior histologic confirmation will initially be screened within confines of a screening consent and only those participants with findings consistent with craniopharyngioma and without findings suggesting an indeterminate lesion or lesion of an alternative diagnosis (including abnormal tumor markers found in blood or CSF, if completed as part of SOC work-up or if lesion concerning for alternate diagnosis) will move ahead with enrollment on the treatment protocol.
• Participants should be surgical candidates for biopsy or resection. If participants are not surgical candidates, but have available archival tumor tissue, they will be enrolled into the exploratory cohort.
• Participants must be willing to provide archival tissue, a minimum of 10-20 paraffin embedded unstained slides OR 1 block with tumor content of 40% or greater is required. Participants who do not meet this criteria may be discussed on a case-by-case basis with the Study Chair(s).
• Participants can have been previously treated with surgical resection alone, cyst drainage and biopsy alone, radiation therapy, other systemic therapies, or any combination thereof.
• Prior Therapy:
• Had their last dose of myelosuppressive chemotherapy \>= 21 days prior to study registration (\>=42 days if nitrosourea therapy).
• Had their last dose of hematopoietic growth factor \>=14 days (long-acting growth factor) or \>=7 days (short-acting growth factor) prior to study registration, or beyond the time during which adverse events (AEs) are known to occur.
• Had their last dose of biologic (anti-neoplastic agent) \>=7 days prior to study registration, or beyond the time during which AEs are known to occur.
• Had their last dose of monoclonal antibodies \>=21 days prior to study registration.
• Radiation:

You may not qualify if:

• Newly Diagnosed Participants:
• \- Participants should not have undergone any previous tumor-directed therapy.
• Recurrent Participants:
• Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from acute adverse events due to agents administered more than 4 weeks earlier.
• Participants must be at least 1 week since the completion of therapy with a biologic or small molecule agent. For any agent with known adverse events that can occur beyond 1 week after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur. Such participants should also be discussed with study chairs.
• Participants should not have previously received any RAS-pathway, but have not received Tovorafenib will be eligible.
• All Participants:
• Rapidly progressive symptoms that require urgent surgery or radiation therapy, which would prevent central review and or preclude participation with tumor-directed medical management alone.
• Uncontrolled symptoms of neuroendocrine dysfunction such as diabetes insipidus, hypothyroidism, panhypopituitarism (participants can be on supplemental medications for hormonal repletion; however, should be on controlled doses for at least 2 weeks prior to enrollment).
• Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to registration, ongoing cardiomyopathy, or current prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF) interval \> 440 ms based on triplicate ECG average.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to tovorafenib.
• Nausea and vomiting \>= Grade 2, malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude adequate absorption.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
• Participants who are receiving any other investigational agents.
• Women of childbearing potential must not be pregnant or breast-feeding.

Sponsors & Collaborators

• Sabine Mueller, MD, PhD: lead
• Day One Biopharmaceuticals, Inc.: collaborator

Study Sites (20)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

RECRUITING

Rady Children's Hospital/University of California, San Diego

San Diego, California, 92037, United States

RECRUITING

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

University of Florida

Gainesville, Florida, 32611, United States

RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

RECRUITING

Riley Hospital for Children at Indiana University Health

Indianapolis, Indiana, 46202, United States

RECRUITING

John Hopkins University

Baltimore, Maryland, 21218, United States

RECRUITING

Dana-Farber/Boston Children's Harvard Medical School

Boston, Massachusetts, 02215, United States

RECRUITING

University of Michigan

Ann Arbor, Michigan, 48109, United States

RECRUITING

Children's Minnesota

Minneapolis, Minnesota, 55404, United States

RECRUITING

St. Louis Children's Hospital Washington University

St Louis, Missouri, 63110, United States

RECRUITING

NYU Langone Health

New York, New York, 10016, United States

RECRUITING

Duke University Medical Center

Durham, North Carolina, 27710, United States

RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19103, United States

RECRUITING

University of Utah

Salt Lake City, Utah, 84112, United States

RECRUITING

John Hunter Children's Hospital

New Lambton Heights, New South Wales, 2310, Australia

RECRUITING

Royal Hobart Hospital

Hobart, Tasmania, 7000, Australia

RECRUITING

Children's Cancer Centre, Monash Children's Hospital

Clayton, VIC 3168, Australia

RECRUITING

Royal Children's Hospital, Childrens' Cancer Centre

Parkville, Victoria, 3052, Australia

RECRUITING

Perth Children's Hospital

Nedlands, Western Australia, 6009, Australia

RECRUITING

MeSH Terms

Conditions

Craniopharyngioma

Interventions

tovorafenib

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Study Officials

• Sabine Mueller, MD, PhD, MAS

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Cassie Kline, MD

  Children's Hospital of Philadelphia

  STUDY CHAIR

Central Study Contacts

PNOC Operations Office

CONTACT

877-827-3222; PNOC029@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 15, 2022
• First Posted: July 19, 2022
• Study Start: September 12, 2022
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2028
• Last Updated: April 23, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

US (15); AU (5)