Using Tovorafenib to treat craniopharyngioma in children and young adults

Tovorafenib for the Treatment of Newly Diagnosed or Recurrent Craniopharyngioma in Children and Young Adults

This study is testing if a new drug called Tovorafenib can safely help children and young adults with craniopharyngioma live better and longer without their cancer getting worse.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 57 (estimated)
• Ages: 1 Year to 39 Years
• Sex: All
• Sponsor: University of California, San Francisco (Academic / other)
• Drugs / interventions: chemotherapy, radiation
• Locations: 20 sites (Birmingham, Alabama and 19 other locations)
• Trial ID: NCT05465174 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety and effectiveness of Tovorafenib, a pan-RAF-kinase inhibitor, for treating craniopharyngioma in children and young adults. The primary goal is to assess progression-free survival and quality of life over 12 months, comparing results to historical controls. Secondary objectives include monitoring visual and neuroendocrine deficits over three years, while exploratory objectives involve analyzing tumor tissue for changes in cellular and protein characteristics throughout treatment. Participants will be closely monitored for their response to the therapy and any potential side effects.

Who should consider this trial

Good fit: Ideal candidates are children and young adults with newly diagnosed or recurrent craniopharyngioma who are surgical candidates.

Not a fit: Patients with alternative diagnoses or those who are not surgical candidates may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve survival rates and quality of life for young patients with craniopharyngioma.

How similar studies have performed: While this approach is novel, similar studies targeting other tumors with RAF inhibitors have shown promising results.

Eligibility criteria

Inclusion Criteria:

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:

* Had their last fraction of local irradiation to primary tumor \>=12 weeks prior to registration; investigators are reminded to review potentially eligible cases to avoid confusion with pseudo-progression.
* At least 14 days after local palliative radiation (small-port).

All Participants:

* Age 1 to 39 years.
* Participants continuing on maintenance therapy after standard of care biopsy/resection must have measurable disease, as defined as lesions that can be accurately measured in two dimensions (longest diameter to be recorded) with a minimum size of no less than double the slice thickness. Previously irradiated lesions are considered non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy. Participants without measurable disease may continue on study and will be followed for study endpoints, but will not be included as part of target accrual.
* Performance Score: Karnofsky \>= 50 for participants \> 16 years of age and Lansky \>= 50 for participants \<= 16 years of age. Participants 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.
* Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration. The participant steroid dose should be no more than a steroid-equivalent of dexamethasone 0.1 mg/kg/day (or maximum 4mg/day; whichever is the lower dose) at time of enrollment. Participants that have been stable on physiologic hormone replacement for hypopituitarism are allowed.
* Organ Function Requirements:

  * Adequate Bone Marrow Function defined as:

    * Peripheral absolute neutrophil count (ANC) \>=1000/mm3.
    * Platelet count \>= 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
  * Adequate Renal Function defined as-

    ---A serum creatinine \< 1.5 Upper Limit normal (ULN) based on age and gender.
  * Adequate Liver Function defined as-

    * Bilirubin (sum of conjugated + unconjugated) \<= 1.5 x upper limit of normal (ULN) for age (except in participants with documented Gilbert syndrome).
    * Serum glutamic-pyruvic transaminase (SGPT)((alanine aminotransferase (ALT)) \<= 3 x ULN.
    * Serum albumin \>=2 g/dL (20g/L).
  * Adequate Neurologic Function defined as participants with seizure disorder may be enrolled if well controlled. Participants on non-enzyme inducing anticonvulsants may be excluded pending interaction(s) with study drug.
  * Adequate Pulmonary Function defined as no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of \> 92% while breathing room air.
  * prothrombin time (PT) /partial thromboplastin time (PTT)/International Normalized Ratio (INR) within institutional normal limits or deemed appropriate for surgical intervention by the treating team for patients undergoing surgery biopsy/resection
* The effects of Tovorafenib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (non-hormonal contraception; barrier method of birth control; abstinence - note, tovorafenib can make hormonal contraceptives ineffective) prior to study entry, for the duration of study participation and 28 days after completion of Tovorafenib administration, whichever is later. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* A legal parent/guardian or participants must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
* Ability to complete the PedsQL Core Module.
* Patients must enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution.

Exclusion Criteria:

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.
* Current treatment with a strong cytochrome P4502C8(CYP2C8) inhibitor or inducer other than those allowed per Section 5.6.1. Medications that are substrates of CYP2C8 are allowed but should be used with caution.
* Participants with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.

Where this trial is running

Birmingham, Alabama and 19 other locations

• University of Alabama at Birmingham — Birmingham, Alabama, United States (Recruiting)
• Rady Children's Hospital/University of California, San Diego — San Diego, California, United States (Recruiting)
• University of California, San Francisco — San Francisco, California, United States (Recruiting)
• University of Florida — Gainesville, Florida, United States (Recruiting)
• Ann & Robert H. Lurie Children's Hospital of Chicago — Chicago, Illinois, United States (Recruiting)
• Riley Hospital for Children at Indiana University Health — Indianapolis, Indiana, United States (Recruiting)
• John Hopkins University — Baltimore, Maryland, United States (Recruiting)
• Dana-Farber/Boston Children's Harvard Medical School — Boston, Massachusetts, United States (Recruiting)
• University of Michigan — Ann Arbor, Michigan, United States (Recruiting)
• Children's Minnesota — Minneapolis, Minnesota, United States (Recruiting)
• St. Louis Children's Hospital Washington University — St Louis, Missouri, United States (Recruiting)
• NYU Langone Health — New York, New York, United States (Recruiting)
• Duke University Medical Center — Durham, North Carolina, United States (Recruiting)
• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States (Recruiting)
• University of Utah — Salt Lake City, Utah, United States (Recruiting)
• John Hunter Children's Hospital — New Lambton Heights, New South Wales, Australia (Recruiting)
• Royal Hobart Hospital — Hobart, Tasmania, Australia (Recruiting)
• Children's Cancer Centre, Monash Children's Hospital — Clayton, Vic 3168, Australia (Recruiting)
• Royal Children's Hospital, Childrens' Cancer Centre — Parkville, Victoria, Australia (Recruiting)
• Perth Children's Hospital — Nedlands, Western Australia, Australia (Recruiting)

Study contacts

• Principal investigator: Sabine Mueller, MD, PhD, MAS — University of California, San Francisco
• Study coordinator: PNOC Operations Office

Conditions Craniopharyngioma, Child; Craniopharyngioma; Recurrent Craniopharyngioma; Neoadjuvant therapy