PNOC029_Tovorafenib for the treatment of newly diagnosed or recurrent craniopharyngioma in children and young adults

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prinses Maxima Centrum voor Kinderoncologie B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-03-30

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-511510-20-00

ClinicalTrials.gov

NCT05465174

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To determine progression free survival at 12 months and maintenance of quality of life at 12 months as based on physical function as compared to historical controls.

Secondary objectives 2

1. To identify proportion of participants with visual deficits at 1-year, 2-year, and 3-year follow-up
2. To identify proportion of participants with neuroendocrine deficits at 1-year, 2-year, and 3-year follow-up

Conditions and MedDRA coding

craniopharyngioma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 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.
2. 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. 3.3.2. 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
4. 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.
5. 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
6. 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)
7. 3.3.3. All Participants: Age 1 to 39 years
8. 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).
9. 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.
10. 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.
11. 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.
12. 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
13. 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.
14. 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.
15. 3.3.1. Newly Diagnosed Participants: Participants must be surgical candidates for biopsy or resection and planned for standard of care biopsy or resection.
16. 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).
17. 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.

Exclusion criteria 14

1. 3.4.1. Newly Diagnosed Participants: Patient should not have undergone any previous tumor-directed therapy.
2. 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. 3.4.3. All Participants: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
4. 3.4.3. All Participants: Participants who are receiving any other investigational agents.
5. 3.4.3. All Participants: Women of childbearing potential must not be pregnant or breast-feeding.
6. 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.
7. 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.
8. 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
9. 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.
10. 3.4.2. Recurrent Participants: Participants who have have previously received any RAS-pathway, but have not received tovorafenib will be eligible.
11. 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.
12. 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).
13. 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.
14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. PFS12 (progression free survival at 12 months)
2. QOL12 (quality of life at 12 months)

Secondary endpoints 5

1. Visual Responsive ≥ 0.2 logMAR improvement in VA compared to baseline
2. Stable VA = does not meet criteria for Improved or Worsening VA compared to baseline
3. Visual Progressive Disease ≥ 0.2 logMAR worsening compared to baseline
4. Visual field assessments with Humphrey visual field test
5. Presence or absence of new from baseline: hypothalamic obesity, diabetes insipidus, growth hormone deficiency, adrenal insufficiency

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prinses Maxima Centrum voor Kinderoncologie B.V.

Sponsor organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Dr. Jasper van der Lugt

Public contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Secretariat TDC

Third parties 1

Locations

3 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 57 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications