Anaplastic Astrocytoma, Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3K27-altered, Glioblastoma, Glioblastoma Multiforme, High Grade Glioma, Infant Type Hemispheric Glioma, WHO Grade III Glioma, WHO Grade IV Glioma
Conditions
Keywords
ALK fusion, ROS fusion, High Grade Glioma, Diffuse Intrinsic Pontine Glioma
Brief summary
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.
Detailed description
This is a multi-institutional clinical trial of lorlatinib in children newly diagnosed with High Grade Glioma (HGG) harboring ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) or ALK (anaplastic lymphoma kinase) fusions. In this pilot study, investigators will assess the disease control rate (Continued Complete Response (CCR), Complete Response (CR), Partial Response (PR), and Stable Disease (SD)) of lorlatinib, and feasibility and safety of lorlatinib administration in combination with standard chemotherapy in children with newly diagnosed HGG with ROS or ALK fusions who receive 2 cycles of lorlatinib administered orally, once daily, at 115 mg/m2/day (or maximum of 200mg/dose) for pediatric patients, and 150mg/dose for patients \>18 years, continuously. Secondary objectives include overall survival (OS) and progression free survival (PFS) lorlatinib as a single agent and in combination with standard chemotherapy used in children ≤ 48 months with HGG, or post focal radiotherapy in children \> 48 months of age. Children with HGG who have a CCR or CR after 2 cycles of therapy will continue to receive single agent lorlatinib for a total of 12xs 28-day cycles. Continuation of treatment beyond 12 cycles, and up to maximum 26 cycles, may be considered for patients on lorlatinib monotherapy if they are receiving clinical benefit from the study, at the discretion of the treating physician after discussion with Study Chairs. Patients with PR or SD after 2 cycles of lorlatinib monotherapy will go on to receive lorlatinib either in combination with standard backbone chemotherapy (BABYPOG or HIT-SKK, investigator's choice) or post standard radiotherapy, based on the patient's age. Patients with PD after 2 cycles will be taken off protocol therapy. This study will be a part of the TarGeT, molecularly-guided umbrealla trial in children, adolescents, and young adults newly diagnosed with HGG, including diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG). Patients will undergo (1) upfront comprehensive tumor molecular profiling using multi-omic approach with rapid return of results, (2) stratification to biologically-targeted treatment arms to assess treatment efficacy, and (3) longitudinal evaluation of peripheral blood, cerebrospinal fluid (CSF), and/or tumor tissue as well as neuro-imaging to identify biomarkers predictive of response, recurrence, and resistance. Based on recent trials conducted in this patient population, investigators conservatively estimate that 1 child with newly diagnosed DIPG or HGG with either ROS1 or ALK fusion will be enrolled every 2 months on this study. Patients ≤18 years will start at the recommended phase 2 dose of 115 mg/m2/day and patients \>18 years will start at 150mg/dose. All patients will be treated continuously for 28 days, and one dose de-de-escalations will be allowed. A maximum of 15 eligible patients will be enrolled, anticipated over 2.5 years.
Interventions
DRUGLorlatinib
Continue maintenance monotherapy for total 12 cycles
DRUGLorlatinib with chemotherapy1
Continue lorlatinib with BABY-POG chemotherapy backbone for 72 weeks
DRUGLorlatinib with chemotherapy 2
Continue lorlatinib with HIT-SKK chemotherapy backbone for 42 weeks
DRUGLorlatinib post Radiation
Continue lorlatinib monotherapy 28 days post completion of radiation therapy for 12 cycles
Sponsors
Nationwide Children's Hospital
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Feasibility
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
Yes
Inclusion criteria
1. Patients must be ≥ 12 months and ≤ 21 years of age at the time of study enrollment on TarGeT-SCR. 2. 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. 3. 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. 4. 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. 5. Prior Therapy: * Patients must not have received any prior anti-cancer chemotherapy. * Prior use of corticosteroids is allowed (see below
Exclusion criteria
) 6. 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). 6.5Adequate 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. 6.7 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate | Day 1 of treatment until the end of cycle 2 (each cycle is 28 days) | To assess the disease control rate (Complete Response \[CR\], Continued Complete Response \[CCR\], Partial Response \[PR\] and Stable Disease \[SD\]) of lorlatinib in young children with newly diagnosed high-grade glioma with ALK or ROS1 fusion after 2 cycles of lorlatinib monotherapy. |
| Number of participants with lorlatinib-related adverse events as assessed by CTCAE v5.0 | From Day 1 of protocol treatment through 30 days following end of protocol treatment | Assess and further characterize the safety and toxicity of lorlatinib in pediatric patients newly diagnosed with HGG with a fusion in ALK or ROS. This will be achieved by calculating the number of participants with, as well as frequency and severity of, lorlatinib-related Adverse Events as assessed by CTCAE v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Associations between genomic tumor alterations with radiographic response | From diagnosis through the end of follow-up period. | Explore longitudinal associations of genomic, transcriptomic, epigenetic, and/or immunologic alterations of tumor at diagnosis, recurrence, or autopsy with radiographic response and advanced neuro-imaging measures. |
| Objective Response Rate (ORR) in HGG | From Day 1 of protocol treatment through 30 days following end of protocol treatment | To assess the objective response rate (ORR) (Complete Response \[CR\] and Partial Response \[PR\]) of lorlatinib in children with newly diagnosed high-grade glioma with ALK or ROS1 fusion after 2 cycles of lorlatinib monotherapy. |
| Overall Survival (OS) in HGG | Day 1 of treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months | To assess overall (OS) of children with high-grade gliomas treated with a lorlatinib-containing regimen at 1, 3 and 5 years and compare it to historical data from BABYPOG and HIT-SKK. |
| Progression-Free Survival in HGG | Day 1 of treatment until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up to 5 years | To assess progression-free survival (PFS) of children with high-grade gliomas treated with a lorlatinib-containing regimen at 1, 3 and 5 years and compare it to historical data from BABYPOG and HIT-SKK. |
Countries
Australia, Canada, Germany, Netherlands, New Zealand, United States
Contacts
CONTACTKelsey H Troyer, PhD
STUDY_CHAIRHamza Gorsi, MD
Children's Hospital of Michigan
STUDY_CHAIRSusan Chi, MD
Dana-Farber Cancer Institute
PRINCIPAL_INVESTIGATORMaryam Fouladi, MD
Nationwide Children's Hospital
Outcome results
None listed