A Pilot Study of Lorlatinib for Treatment of Children With Newly Diagnosed High-Grade Glioma With ROS-1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) or ALK (Anaplastic Lymphoma Kinase) Fusion
The goal of this study is to determine the response of the study drug loratinib in treating children who are newly diagnosed high-grade glioma with a fusion in ALK or ROS1. It will also evaluate the safety of lorlatinib when given with chemotherapy or after radiation therapy.
⁃ Patients must be ≥ 12 months and ≤ 21 years of age at the time of study enrollment on TarGeT-SCR.
⁃ Diagnosis:
⁃ Patients with newly diagnosed high-grade glioma (HGG), including diffuse intrinsic pontine gliomas (DIPG), whose tumors harbor an ALK or ROS-1 fusion alteration are eligible. Patients must have had histologically verified high-grade glioma from diagnostic biopsy or resection. For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO Grade 2-4. All other HGGs must be Grade 3 or 4.
⁃ Disease Status:
⁃ Patients with disseminated DIPG or HGG are eligible only if the patient is to receive chemotherapy only, i.e. no craniospinal RT is intended to be given. MRI of spine must be performed if disseminated disease is suspected clinically by the treating physicians. Patients with primary spinal tumors are eligible only if the patient is to receive either chemotherapy or focal radiation therapy, i.e., no craniospinal RT is intended to be given. Patients with leptomeningeal disease only, with no definitive identifiable primary tumor, and documented ALK or ROS-1 fusion, must be discussed with the Study Chair on a case-by-case basis.
⁃ Performance Level:
⁃ Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). 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 not have received any prior anti-cancer chemotherapy.
‣ Prior use of corticosteroids is allowed (see below Exclusion Criteria)
⁃ Organ Function Requirements 6.1 Adequate Bone Marrow Function Defined as:
∙ Peripheral absolute neutrophil count (ANC) ≥ 1000/μL
‣ Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
‣ Hemoglobin \>8 g/dL (may receive transfusions) 6.2 Adequate Renal Function Defined as:
‣ Serum creatinine within normal institutional limits OR Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 6.3 Adequate Liver Function Defined as:
‣ Total bilirubin ≤ 2 × institutional upper limit of normal
‣ AST(aspartate aminotransferase)/ALT(alanine transaminase) ≤ 2.5 × institutional upper limit of normal 6.4 Adequate Pulmonary Function Defined as: Pulse oximetry \> 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest).
• 5Adequate Cardiac Function Defined as: QTc ≤ 470 msec (by Bazett formula) 6.6 Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
• 7 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