Efficacy and Safety of Tovorafenib in Children and Young Adults with Newly Diagnosed or Recurrent Craniopharyngioma

Trial ID: 2024-511510-20-00
Sponsor: Princess Maxima Center For Pediatric Oncology

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Diseases & Conditions

Craniopharyngioma

Objectives

The primary objective of this study is to evaluate the progression-free survival at 12 months and the maintenance of quality of life regarding physical function at 12 months in pediatric and young adult patients with newly diagnosed or recurrent craniopharyngioma, compared to historical controls. Secondary objectives include the assessment of the following outcomes at 1-year, 2-year, and 3-year follow-up:

Proportion of participants with visual deficits.
Proportion of participants with neuroendocrine deficits.

Trial scope: 3, 4, 5.

Participants

This clinical trial involves 41 participants diagnosed with craniopharyngioma. The study population consists of individuals aged 1 to 39 years, including both males and females. Participants may present with either newly diagnosed or recurrent disease. Inclusion requires a Karnofsky performance score of ≥ 50 for those over 16 years of age or a Lansky scale score of ≥ 50 for those 16 years of age or younger. Eligible individuals must demonstrate adequate bone marrow function, renal function, hepatic function, neurologic function, and pulmonary function. Specifically, participants must maintain a stable or decreasing dose of dexamethasone and meet established thresholds for absolute neutrophil count, platelet count, serum creatinine, and bilirubin. For those with recurrent disease, requirements include specific intervals following prior chemotherapy, hematopoietic growth factors, biologics, or radiation therapy. Additionally, participants must be surgical candidates for biopsy or resection, or possess available archival tumor tissue. Women of child-bearing potential and men are required to utilize adequate contraception due to unknown effects on the developing fetus.

Plans and Procedures

This Phase II clinical trial is designed to evaluate the safety and efficacy of tovorafenib in pediatric and young adult patients with craniopharyngioma. The study includes both newly diagnosed and recurrent cases. The primary objectives are to determine progression free survival at 12 months and to assess the maintenance of quality of life at 12 months compared to historical controls. The study methodology involves a screening visit to confirm the diagnosis via imaging or histology and to ensure adherence to specific organ function, performance score, and corticosteroid requirements. Following enrollment, participants receive tovorafenib administered as an oral suspension or tablet. The trial includes follow-up assessments to monitor secondary endpoints, such as visual acuity, visual field assessments, and the development of endocrine complications like diabetes insipidus or growth hormone deficiency. Participants must adhere to strict contraception protocols during the study and for 28 days following the final dose. The overall study duration is estimated to continue through October 2034. Early termination from the study may occur based on clinical requirements or safety considerations.

Treatment

The experimental treatment consists of tovorafenib, an orphan drug administered in two different pharmaceutical forms. The first form is a powder for oral suspension, and the second form is a tablet. Both formulations are administered via the oral route at a dosage of 600 mg.

Efficacy

The efficacy of tovorafenib in the treatment of craniopharyngioma is assessed using several predefined endpoints. The primary efficacy parameters include progression-free survival at 12 months (PFS12) and the maintenance of quality of life at 12 months (QOL12) based on physical function, which are compared against historical controls.

Secondary efficacy assessments involve the evaluation of visual acuity (VA) to determine visual responsive (improvement of ≥ 0.2 logMAR), stable VA, or visual progressive disease (worsening of ≥ 0.2 logMAR) relative to baseline. Visual field assessments are conducted using the Humphrey visual field test. Additionally, the occurrence of new clinical conditions from baseline is monitored, specifically hypothalamic obesity, diabetes insipidus, growth hormone deficiency, and adrenal insufficiency.

Inclusion and Exclusion Criteria

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Inclusion Criteria

3.3.1. 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 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. Additionally, for patients 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 patients will also be considered eligible. Patients beyond 6 weeks of radiographic diagnosis should be discussed with study chairs.
3.3.2. Recurrent Participants: 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.
3.3.2. Recurrent Participants: 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
3.3.2. Recurrent Participants: Participants can have been previously treated with surgical resection alone, cyst drainage and biopsy alone, radiation therapy, other systemic therapies, or any combination thereof.
3.3.2. Recurrent Participants: 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
3.3.2. Recurrent Participants: 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)
3.3.3. All Participants: Age 1 to 39 years
3.3.2. Recurrent Participants: 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).
3.3.3. All Participants: 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.
3.3.3. All Participants: Performance Score: Karnofsky ≥ 50 for participants > 16 years of age and Lansky ≥ 50 for participants ≤ 16 years of age (See Appendix A). 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.
3.3.3. All Participants: Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration. The patient 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 physiologichormone replacement for hypopituitarism are allowed.
3.3.3. All Participants: 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 patients with documented Gilber syndrome). - SGPT ((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. See Appendix B for a list of recommended non-enzyme inducing anticonvulsants. • 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. - PT/PTT/INR within institutional normal limits or deemed appropriate for surgical intervention by the treating team for patients undergoing surgery biopsy/resection
3.3.3. All Participants: 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.
3.3.3. All Participants: A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
3.3.1. Newly Diagnosed Participants: Participants must be surgical candidates for biopsy or resection and planned for standard of care biopsy or resection.
3.3.2. Recurrent Participants: Recurrent craniopharyngioma, as based on histologic confirmation at time of initial diagnosis (participants with ACP will only be eligible for the recurrent arm).
3.3.3. All participants: All Participants: Ability to complete the PedsQL Core Module. Patients must enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution.

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Exclusion Criteria

3.4.1. Newly Diagnosed Participants: Patient should not have undergone any previous tumor-directed therapy.
3.4.3. All Participants: Nausea and vomiting≥ Grade 2, malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude adequate absorption.
3.4.3. All Participants: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
3.4.3. All Participants: Participants who are receiving any other investigational agents.
3.4.3. All Participants: Women of childbearing potential must not be pregnant or breast-feeding.
3.4.3. All Participants: 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.
3.4.2. 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.
3.4.3. All Participants: Participants with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
3.4.2. Recurrent Participants: 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.
3.4.2. Recurrent Participants: Participants who have have previously received any RAS-pathway, but have not received tovorafenib will be eligible.
3.4.3. 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.
3.4.3. All Participants: Uncontrolled symptoms of neuroendocrine dysfunction such as diabetes insipidus, hypothyroidism, panhypopituatarism (participants can be on supplemental medications for hormonal repletion; however, should be on controlled doses for at least 2 weeks prior to enrollment).
3.4.3. All Participants: 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.
3.4.3. All Participants: History of allergic reactions attributed to compounds of similar chemical or biologic composition to tovorafenib or other agents used in study.