Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion

Early Phase 1

Active, not recruiting

• Conditions: Glioblastoma Multiforme; WHO Grade IV Glioma; Diffuse Midline Glioma, H3K27-altered; High Grade Glioma; Diffuse Intrinsic Pontine Glioma; Infant Type Hemispheric Glioma; Anaplastic Astrocytoma; Glioblastoma; WHO Grade III Glioma
• Interventions: Drug: Lorlatinib; Drug: Lorlatinib with chemotherapy1; Drug: Lorlatinib with chemotherapy 2; Drug: Lorlatinib post Radiation

• Registration Number: NCT06333899
• Lead Sponsor: Nationwide Children's Hospital

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.

Study Timeline

• Study First Submitted: 2024-03-14
• Study First Submitted QC: 2024-03-20
• Study First Posted: 2024-03-27
• Status Verified: 2025-05
• Study Start: 2025-08-03
• Last Update Submitted: 2025-10-27
• Last Update Posted: 2025-10-29
• Primary Completion: 2029-07-01
• Study Completion: 2035-06-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 15

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

Exclusion Criteria

1. 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.

   Females of reproductive potential must use an effective non-hormonal method of contraception, since lorlatinib can render hormonal contraceptives ineffective, during study treatment and for at least 6 months after the final dose. Males with female partners of reproductive potential must use effective contraception during treatment with lorlatinib and for 3 months after the final dose.

2. Concomitant Medications

   • Investigational Agents/Drugs: Patients who have previously received or are currently receiving another investigational drug are not eligible.
   • Anti-cancer Agents: Patients who have previously received or are currently receiving other anti-cancer agents, including chemotherapy, immunotherapy, monoclonal antibodies, biologic or targeted therapy, are not eligible

3. Infection: Patients must not have any active, uncontrolled systemic bacterial, viral or fungal infection.

4. Patients who have received prior solid organ transplantation are not eligible.

5. Patients must not have malabsorption syndrome or other condition affecting oral absorption.

6. Patients must not be receiving any treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to treatment with loraltinib. Moderate inducers of CYP3A4 should be avoided

7. Avoid concomitant use of lorlatinib with certain CYP3A substrates, for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.

8. P-glycoprotein (P-gp) substrates: Lorlatinib is considered a moderate P-gp inducer. Co-administration of lorlatinib with P-gp substrates including but not limited to digoxin should be avoided as the concentration of these drugs may be reduced by lorlatinib.

9. 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.

10. Patients with a known personal history of acute or chronic severe psychiatric disorders or current history of suicidal ideation and history of suicide attempt.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lorlatinib Monotherapy	Lorlatinib	Lorlatinib administered as monotherapy by PO (per os) or NG (nasogastric) for two 28-day cycles at 115 mg/m2/day (or maximum 200mg/dose), after which disease evaluation by Magnetic Resonance Imaging (MRI) imaging will be performed.
Lorlatinib Combination with BABY POG chemotherapy	Lorlatinib with chemotherapy1	Lorlatinib monotherapy x2 cycles followed by maintenance therapy with lorlatinib (115 mg/m2/day) and BABY-POG chemotherapy backbone (vincristine, cyclophosphamide, cisplatin) The BABYPOG chemotherapy backbone regimen will consist of six 12-week courses. Each course will consist of cycles A, A2 and B, which will be administered consecutively, in 28-day cycles for a total of 72 weeks
Lorlatinib Combination with HIT-SKK chemotherapy	Lorlatinib with chemotherapy 2	Lorlatinib monotherapy x2 cycles followed by maintenance therapy with lorlatinib (115 mg/m2/day) and HIT-SKK chemotherapy backbone (cyclophosphamide, vincristine, methotrexate, carboplatin, etposide) The recommended HIT-SKK chemotherapy backbone regimen consists of modular chemotherapy cycles, three courses of 4 blocks each (Element IIS, Element IIIS/1, Element IIIS/2, and Element IVS). Each element will be administered consecutively at 2-3-week intervals. Elements IIS and IVS cycles will be repeated twice thereafter. The entire length of treatment for HIT-SKK will be approximately 42 weeks.
Lorlatinib Maintenance Therapy post RT	Lorlatinib post Radiation	Lorlatinib monotherapy x2 cycles followed by Radiation Therapy and continue lorlatnib maintenance monotherapy (115 mg/m2/day) 28 days post completion of RT for 12 cycles
Lorlatinib Combination with BABY POG chemotherapy	Lorlatinib	Lorlatinib monotherapy x2 cycles followed by maintenance therapy with lorlatinib (115 mg/m2/day) and BABY-POG chemotherapy backbone (vincristine, cyclophosphamide, cisplatin) The BABYPOG chemotherapy backbone regimen will consist of six 12-week courses. Each course will consist of cycles A, A2 and B, which will be administered consecutively, in 28-day cycles for a total of 72 weeks
Lorlatinib Combination with HIT-SKK chemotherapy	Lorlatinib	Lorlatinib monotherapy x2 cycles followed by maintenance therapy with lorlatinib (115 mg/m2/day) and HIT-SKK chemotherapy backbone (cyclophosphamide, vincristine, methotrexate, carboplatin, etposide) The recommended HIT-SKK chemotherapy backbone regimen consists of modular chemotherapy cycles, three courses of 4 blocks each (Element IIS, Element IIIS/1, Element IIIS/2, and Element IVS). Each element will be administered consecutively at 2-3-week intervals. Elements IIS and IVS cycles will be repeated twice thereafter. The entire length of treatment for HIT-SKK will be approximately 42 weeks.
Lorlatinib Maintenance Therapy post RT	Lorlatinib	Lorlatinib monotherapy x2 cycles followed by Radiation Therapy and continue lorlatnib maintenance monotherapy (115 mg/m2/day) 28 days post completion of RT for 12 cycles

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.

Trial Locations

Locations (17)

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Children's National Medical Center; 🇺🇸 Washington D.C., District of Columbia, United States

Ann & Robert H. Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Duke University Health System; 🇺🇸 Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Texas Children's Hospital; 🇺🇸 Houston, Texas, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

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