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

NCT06333899 | Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: CONNECT TarGeT-LR01FD008167
• Study Type: interventional
• Target: 15
• Locations: 6 countries
• Sites: 18

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.

Conditions

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

Keywords

ALK fusion; ROS fusion; High Grade Glioma; Diffuse Intrinsic Pontine Glioma

Outcome Measures

Primary Outcomes (2)

• 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.

  Day 1 of 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 Outcomes (4)

• Objective Response Rate (ORR) in HGG

  From Day 1 of protocol treatment through 30 days following end of protocol treatment

• 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

• 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

• Associations between genomic tumor alterations with radiographic response

  From diagnosis through the end of follow-up period.

Study Arms (4)

Lorlatinib Monotherapy

EXPERIMENTAL

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

Lorlatinib Combination with BABY POG chemotherapy

EXPERIMENTAL

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; Drug: Lorlatinib with chemotherapy1

Lorlatinib Combination with HIT-SKK chemotherapy

EXPERIMENTAL

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; Drug: Lorlatinib with chemotherapy 2

Lorlatinib Maintenance Therapy post RT

EXPERIMENTAL

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; Drug: Lorlatinib post Radiation

Interventions

Lorlatinib post Radiation DRUG

Continue lorlatinib monotherapy 28 days post completion of radiation therapy for 12 cycles

Also known as: LOBRENA

Lorlatinib Maintenance Therapy post RT

Lorlatinib DRUG

Continue maintenance monotherapy for total 12 cycles

Also known as: LOBRENA

Lorlatinib Combination with BABY POG chemotherapy; Lorlatinib Combination with HIT-SKK chemotherapy; Lorlatinib Maintenance Therapy post RT; Lorlatinib Monotherapy

Lorlatinib with chemotherapy1 DRUG

Continue lorlatinib with BABY-POG chemotherapy backbone for 72 weeks

Also known as: LOBRENA

Lorlatinib Combination with BABY POG chemotherapy

Lorlatinib with chemotherapy 2 DRUG

Continue lorlatinib with HIT-SKK chemotherapy backbone for 42 weeks

Also known as: LOBRENA

Lorlatinib Combination with HIT-SKK chemotherapy

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Nationwide Children's Hospital: lead
• Pfizer: collaborator

Study Sites (18)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

NOT YET RECRUITING

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

NOT YET RECRUITING

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

Chicago, Illinois, 60611, United States

NOT YET RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

NOT YET RECRUITING

Duke University Health System

Durham, North Carolina, 27708, United States

NOT YET RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Nationwide Children's Hospital

Columbus, Ohio, 43235, United States

NOT YET RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

NOT YET RECRUITING

Texas Children's Hospital

Houston, Texas, 77030, United States

NOT YET RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98105, United States

NOT YET RECRUITING

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

NOT YET RECRUITING

Queensland Children's Hospital

South Brisbane, Queensland, 4101, Australia

NOT YET RECRUITING

Perth Children's Hospital

Perth, Western Australia, 6000, Australia

NOT YET RECRUITING

The Hospital for Sick Children (SickKids)

Toronto, Ontario, M5G1X8, Canada

NOT YET RECRUITING

Montreal Children's Hospital

Montreal, Quebec, H4A3J1, Canada

NOT YET RECRUITING

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

Heidelberg, Baden-Wurttemberg, 69120, Germany

NOT YET RECRUITING

Princess Máxima Center

Utrecht, 3720, Netherlands

NOT YET RECRUITING

Starship Children's Hospital

Auckland, Grafton, 1023, New Zealand

NOT YET RECRUITING

MeSH Terms

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma; Astrocytoma; Glioblastoma

Interventions

lorlatinib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Hamza Gorsi, MD

  Children's Hospital of Michigan

  STUDY CHAIR

• Susan Chi, MD

  Dana-Farber Cancer Institute

  STUDY CHAIR

• Maryam Fouladi, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kelsey H Troyer, PhD

CONTACT

16147223284; kelsey.troyer@nationwidechildrens.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Feasibility

Study Record Dates

• First Submitted: March 14, 2024
• First Posted: March 27, 2024
• Study Start: August 3, 2025
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): June 1, 2035
• Last Updated: March 12, 2026

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

NZ (1); NL (1); DE (1); AU (3); CA (2); US (10)