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

EARLY_PHASE1NOT_YET_RECRUITING

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.

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Study details:

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) 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. 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. 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 will start at the recommended phase 2 dose of 115 mg/m2/day, 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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Patients ≤ 21 years of age (≥ 1 year to ≤ 21 years of age) at the time of study enrollment will be eligible.

Patients with newly diagnosed high-grade (HGG), including diffuse intrinsic pontine gliomas (DIPG), whose tumors are documented in a CLIA/CAP (Clinical Laboratory Improvement Amendments/College of American Pathologists) certified lab (or clinically equivalent method considered standard in non-US sites) to harbor an ALK or ROS-1 fusion alteration by FISH, RT-PCR, or next generation sequencing are eligible. Patients must have had histologically verified high-grade glioma such as anaplastic astrocytoma, glioblastoma, or H3 K27-mutant diffuse midline glioma verified at a CONNECT site.

For sites that do not have have access to CLIA-certified equivalent (certified laboratory) to assess ALK or ROS-1 fusion, testing will be conducted centrally at Nationwide Children's Hospital (NCH). ALK and ROS-1 testing will be performed by Next Generation Sequencing (NGS) using targeted RNA (ribonucleic Acid)-sequencing (Archer Solid Tumor analysis). Please submit 10 unstained sections on charged slides at 10uM thickness, or 10 scrolls cut at 10uM thickness, along with submission of an H&E slide. Formalin-fixed paraffin embedded (FFPE) tissue block and FFPE tissue scroll specimens must contain minimum of 25% tumor Snap-frozen tissue specimens are also acceptable and they must contain a minimum of 10% tumor. Please note that turn-around time for this test is up to 21 days.

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.

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.

Patients must not have received any prior anti-cancer chemotherapy. Prior use of corticosteroids is allowed (see below Exclusion Criteria)

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)

Adequate Renal Function Defined as: Serum creatinine within normal institutional limits OR Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2

Adequate Liver Function Defined as: Total bilirubin ≤ 1.5 × institutional upper limit of normal, AST(aspartate aminotransferase)/ALT(alanine transaminase) ≤ 2.5 × institutional upper limit of normal

Adequate Pulmonary Function Defined as: Pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest).

Adequate Cardiac Function Defined as: QTc ≤ 470 msec (by Bazett formula)

Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.

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

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.

Investigational 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

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

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

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

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 lorlatinib. Moderate inducers of CYP3A4 should be avoided.

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.

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.

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 with a personal history of a psychiatric disorder, other than ADHD, requiring pharmacologic intervention or severe enough to be considered life-threatening.

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Eligibility

Age eligible for study : 1 and older

Healthy volunteers accepted : Yes

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-09-01

Primary completion: 2027-09-01

Study completion finish: 2034-09-01

Study type

TREATMENT

Phase

EARLY_PHASE1

Trial ID

NCT06333899

Intervention or treatment

DRUG: Lorlatinib

DRUG: Lorlatinib with chemotherapy1

DRUG: Lorlatinib with chemotherapy 2

DRUG: Lorlatinib post Radiation

Conditions

• High Grade Glioma
• Diffuse Intrinsic Pontine Glioma
• Glioblastoma
• Glioblastoma Multiforme
• WHO Grade III Glioma
• WHO Grade IV Glioma
• Anaplastic Astrocytoma
• Infant Type Hemispheric Glioma
• Diffuse Midline Glioma, H3K27-altered

Condition: High Grade Glioma, Diffuse Intrinsic Pontine Glioma and more
DRUG: Lorlatinib and other drugs
Randwick, New South Wales, Australia and more
Sponsor: Nationwide Children's Hospital

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Find a site

Closest Location:

Sydney Children's Hospital

Research sites nearby

Select from list below to view details:

Sydney Children's Hospital
Randwick, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Perth Children's Hospital
Perth, Western Australia, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Lorlatinib Monotherapy 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.	DRUG: Lorlatinib Continue maintenance monotherapy for total 12 cycles
EXPERIMENTAL: Lorlatinib Combination with BABY POG chemotherapy 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	DRUG: Lorlatinib Continue maintenance monotherapy for total 12 cycles
EXPERIMENTAL: Lorlatinib Combination with HIT-SKK chemotherapy 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.	DRUG: Lorlatinib Continue maintenance monotherapy for total 12 cycles
EXPERIMENTAL: Lorlatinib Maintenance Therapy post RT 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	DRUG: Lorlatinib Continue maintenance monotherapy for total 12 cycles

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Disease Control Rate	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.	from date on treatment until the end of cycle 2 (each cycle is 28 days)
Number of participants with lorlatinib-related adverse events as assessed by CTCAE v5.0	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	From Day 1 of protocol treatment through 30 days following end of protocol treatment

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Objective Response Rate (ORR) in HGG	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.	From Day 1 of protocol treatment through 30 days following end of protocol treatment
Overall Survival (OS) in HGG	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.	From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
Progression-Free Survival in HGG	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.	From date on treatment until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up to 5 years

Frequently Asked Questions

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References

Clinical Trials Gov: Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion