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

NCT ID: NCT06333899

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

Conditions: Official terms:
Glioblastoma
Glioma
Astrocytoma
Diffuse Intrinsic Pontine Glioma

Conditions: Keywords:
ALK fusion
ROS fusion

Study type: Interventional

Study phase: Early Phase 1

Overall status: Not yet recruiting

Study design:

Allocation: Non-Randomized

Intervention model: Parallel Assignment

Intervention model description: Feasibility

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Drug
Intervention name: Lorlatinib
Description: Continue maintenance monotherapy for total 12 cycles
Arm group label: Lorlatinib Combination with BABY POG chemotherapy
Arm group label: Lorlatinib Combination with HIT-SKK chemotherapy
Arm group label: Lorlatinib Maintenance Therapy post RT
Arm group label: Lorlatinib Monotherapy

Other name: LOBRENA

Intervention type: Drug
Intervention name: Lorlatinib with chemotherapy1
Description: Continue lorlatinib with BABY-POG chemotherapy backbone for 72 weeks
Arm group label: Lorlatinib Combination with BABY POG chemotherapy

Other name: LOBRENA

Intervention type: Drug
Intervention name: Lorlatinib with chemotherapy 2
Description: Continue lorlatinib with HIT-SKK chemotherapy backbone for 42 weeks
Arm group label: Lorlatinib Combination with HIT-SKK chemotherapy

Other name: LOBRENA

Intervention type: Drug
Intervention name: Lorlatinib post Radiation
Description: Continue lorlatinib monotherapy 28 days post completion of radiation therapy for 12 cycles
Arm group label: Lorlatinib Maintenance Therapy post RT

Other name: LOBRENA

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) 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.

Criteria for eligibility:
Criteria:
Inclusion Criteria: 1. Patients ≤ 21 years of age (≥ 1 year to ≤ 21 years of age) at the time of study enrollment will be eligible. 2. Diagnosis: 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. 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 6.1Adequate 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) 6.2Adequate 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 ≤ 1.5 × 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 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 personal history of a psychiatric disorder, other than ADHD, requiring pharmacologic intervention or severe enough to be considered life-threatening.

Gender: All

Minimum age: 1 Year

Maximum age: 21 Years

Healthy volunteers: Accepts Healthy Volunteers

Locations:

Facility:
Name: Children's Hospital Colorado

Address:
City: Aurora
Zip: 80045
Country: United States

Contact:
Last name: Kathleen Dorris, MD
Email: kathleen.dorris@childrenscolorado.org

Facility:
Name: Children's National Medical Center

Address:
City: Washington
Zip: 20010
Country: United States

Contact:
Last name: Eugene Hwang
Email: ehwang@childrensnational.org

Facility:
Name: Ann & Robert H. Lurie Children's Hospital of Chicago

Address:
City: Chicago
Zip: 60611
Country: United States

Contact:
Last name: Ashley Plant, MD
Email: Aplant@luriechildrens.org

Facility:
Name: Dana-Farber Cancer Institute

Address:
City: Boston
Zip: 02215
Country: United States

Contact:
Last name: Susan Chi
Email: Susan_chi@dfci.harvard.edu

Facility:
Name: Duke University Health System

Address:
City: Durham
Zip: 27708
Country: United States

Contact:
Last name: David Ashley, MD
Email: david.ashley@duke.edu

Facility:
Name: Cincinnati Children's Hospital Medical Center

Address:
City: Cincinnati
Zip: 45229
Country: United States

Contact:
Last name: Peter de Blank, MD
Email: Peter.deBlank@cchmc.org

Facility:
Name: Nationwide Children's Hospital

Address:
City: Columbus
Zip: 43235
Country: United States

Contact:
Last name: Maryam Fouladi, MD, MSc
Email: Maryam.fouladi@nationwidechildrens.org

Facility:
Name: Children's Hospital of Philadelphia

Address:
City: Philadelphia
Zip: 19104
Country: United States

Contact:
Last name: Michael J Fisher, MD
Email: fisherm@email.chop.edu

Facility:
Name: Texas Children's Hospital

Address:
City: Houston
Zip: 77030
Country: United States

Contact:
Last name: Patricia Baxter, MD
Email: pabaxter@txch.org

Facility:
Name: Seattle Children's Hospital

Address:
City: Seattle
Zip: 98105
Country: United States

Contact:
Last name: Sarah Leary
Email: sarah.leary@seattlechildrens.org

Facility:
Name: Sydney Children's Hospital

Address:
City: Randwick
Zip: 2031
Country: Australia

Contact:
Last name: David Ziegler, MD
Email: d.ziegler@unsw.edu.au

Facility:
Name: Queensland Children's Hospital

Address:
City: South Brisbane
Zip: 4101
Country: Australia

Contact:
Last name: Tim Hassall, MD
Email: tim.hassall@health.qld.gov.au

Facility:
Name: Perth Children's Hospital

Address:
City: Perth
Zip: 6000
Country: Australia

Contact:
Last name: Nicholas G Gottardo, MBChB
Email: nick.gottardo@health.wa.gov.au

Facility:
Name: The Hospital for Sick Children (SickKids)

Address:
City: Toronto
Zip: M5G1X8
Country: Canada

Contact:
Last name: Eric Bouffet
Email: eric.bouffet@sickkids.ca

Facility:
Name: Montreal Children's Hospital

Address:
City: Montréal
Zip: H4A3J1
Country: Canada

Contact:
Last name: Genevieve Legault, MD
Email: Genevieve.legault4@mcgill.ca

Facility:
Name: Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)

Address:
City: Heidelberg
Zip: 69120
Country: Germany

Contact:
Last name: Olaf Witt, MD
Email: o.witt@kitz-heidelberg.de

Facility:
Name: Princess Máxima Center

Address:
City: Utrecht
Zip: 3720
Country: Netherlands

Contact:
Last name: Jasper van der Lugt
Email: J.vanderLugt@prinsesmaximacentrum.nl

Start date: September 1, 2024

Completion date: September 1, 2034

Lead sponsor:
Agency: Nationwide Children's Hospital
Agency class: Other

Collaborator:
Agency: Pfizer
Agency class: Industry

Source: Nationwide Children's Hospital

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT06333899

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