MEKTOVI® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma

Study Overview
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Brief Summary
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MEKTOVI (binimetinib) is an oral, highly selective reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. The biological activity of binimetinib that has been evaluated bith in vitro and in vivo in a wide variety of tumor types In this Phase II, the drug will be used to treat pediatric patients diagnosed with recurrent Adamantinomatous Craniopharyngioma including patients who have undergone surgery and/or radiation therapy.

Detailed Description
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Adamantinomatous Craniopharyngioma (ACP) is a highly debilitating pediatric brain tumor that lacks medical anti-tumor therapies. Current therapy, which depends largely on surgery and radiation, is associated with poor quality of life and becomes more challenging and risky in the setting of recurrent disease. Recent discoveries regarding the biological characteristics of ACP indicate that available agents, including Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway inhibitors may have efficacy in the control of ACP. Binimetinib is one such agent. In this study, up to 38 patients will receive oral binimetinib at the recommended phase 2 pediatric dose (RP2D) of 32 mg/m2/dose PO every 12 hours for 4 weeks which represents one cycle. Cycles will last 28 days and treatment may continue for up to two years (26 cycles). It will be a multi-center Phase 2 trial with two strata for patients aged >1 year and <25 years with measurable ACP who may have been previously treated with radiation (Stratum 1, 18 patients) or without radiation (Stratum 2, 18 patients).

Official Title
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Phase 2 Study of the MEK Inhibitor MEKTOVI® (Binimetinib) for the Treatment of Pediatric Adamantinomatous Craniopharyngioma

Conditions
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Adamantinous Craniopharyngioma, Recurrent Adamantinomatous Craniopharyngioma

Intervention / Treatment
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* Drug: Binimetinib Oral Tablet [Mektovi]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: Patients must be ≥ 12 months and ≤ 25 years of age at the time of study enrollment. Diagnosis: Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region. Disease Status: Patients must have measurable disease. Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy Stratum 2: Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. Patients 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. Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair Immunotherapy: At least 42 days after the completion of any type of systemic immunotherapy, e.g. tumor vaccines. Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody. Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: a) Focal irradiation > 6 months prior to enrollment and b) No prior craniospinal irradiation is permitted. Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy. Surgery: At least 6 weeks must have elapsed since surgery. 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) Hemoglobin >8 g/dL (may be transfused) Adequate Renal Function Defined as: Creatinine clearance or radioisotope GFR > 70ml/min/1.73 m2 or A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: to < 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to < 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females. Adequate Liver Function Defined as: Total bilirubin ≤ 1.5 × institutional upper limit of normal AST (SGOT) ≤ 2.5 × institutional upper limit of normal ALT (SGPT) ≤ 2.5 × institutional upper limit of normal Adequate Cardiac Function Defined as: Left Ventricular Ejection Fraction greater than the institutional lower limit of normal by echocardiogram QTc ≤ 480 msec (by Bazett formula) Adequate Neurologic Function Defined as: Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies. Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines Exclusion Criteria: Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm. Gastrointestinal Disease: Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation Patients who are unable to swallow, retain or absorb oral medications Concomitant Medications Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible. Study Specific: Patients who have an uncontrolled infection are not eligible. Patients who have received any live or attenuated vaccinations within three months prior to start of therapy are not eligible. Any significant concurrent medical or surgical condition that would jeopardize the patient's safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus or Tuberculosis infection are not eligible. Patients who have received a prior solid organ transplantation are not eligible. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible. Patients who have a history of alcohol, drug, or chemical abuse within 6 months of screening. Patients who have had surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing. Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab and its excipients are not eligible.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: MEKTOVI® (binimetinib)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum 1 and Stratum 2<br>Stratum 1: Patients with progressive or recurrent adamantinomatous craniopharyngiomas following radiation therapy. Stratum 2: Patients with measurable adamantinomatous craniopharyngioma who have undergone surgery but have not previously received radiation therapy. Progressive disease is allowed but not required | Drug: Binimetinib Oral Tablet [Mektovi]<br>* Binimetinib oral continuous dosing 32 mg/m2 PO BID for 4 weeks<br>* Other names: MEKTOVI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained objective response rate of patients with recurrent/progressive previously irradiated ACP to treatment with oral binimetinib | To calculate the number of patients who experience sustained objective response rate [minor response (MR) + partial response (PR) + complete response (CR)] of patients with recurrent/progressive previously irradiated Adamantinomatous Craniopharyngioma to treatment with oral binimetinib (Stratum 1). | From Day 1 of treatment through 30 days following end of protocol treatment | 
| Sustained objective response rate of patients with measurable ACP who have undergone surgery but have not been previously treated with radiation to treatment with oral binimetinib | To calculate the number of patients who experience sustained objective response rate (MR + PR + CR) of patients with measurable Adamantinomatous Craniopharyngioma who have undergone surgery but have not been previously treated with radiation to treatment with oral binimetinib (Stratum 2). | From Day 1 of treatment through 30 days following end of protocol treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biological effects of binimetinib on ACP tumor tissue and cyst fluid. | To measure concentrations of various chemokines including IL-6, IL-8, IL-10 and CXCL1in cyst fluid or tumor or blood of ACP patients treated with binimetinib. Comparisons will be made with known levels in the literature and among patient samples from within the study. | From Day 1 of treatment through 30 days following end of protocol treatment | 
| Toxicities associated with tocilizumab in children with ACP | To calculate the number of participants with, as well as frequency and severity of, binimetinib-related Adverse Events as assessed by CTCAE v5.0 in children with recurrent or refractory ACP | 24 months | 
| PFS of ACP patients treated with binimetinib after radiation | To assess one-year progression-free survival (PFS) rates for patients with ACP who are treated with binimetinib following progression after radiation (Stratum 1). | 12 months | 
| PFS of ACP patients treated with binimetinib who have not received radiation | To assess one-year progression-free survival (PFS) rates for patients with ACP who are treated with binimetinib who have not previously received radiation (Stratum 2). | 12 months |