Clinical trial NCT06333899: Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion
Official title: A Pilot Study of Lorlatinib for Treatment of Children With Newly Diagnosed High-Grade Glioma With ROS-1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) or ALK (Anaplastic Lymphoma Kinase) Fusion
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: EARLY_PHASE1
Conditions: 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
Keywords: ALK fusion
ROS fusion
High Grade Glioma
Diffuse Intrinsic Pontine Glioma
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2024-03-27
Enrollment: 15
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Feasibility
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Disease Control Rate
timeFrame: Day 1 of treatment until the end of cycle 2 (each cycle is 28 days)
measure: Number of participants with lorlatinib-related adverse events as assessed by CTCAE v5.0
timeFrame: From Day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary outcomes:
measure: Objective Response Rate (ORR) in HGG
timeFrame: From Day 1 of protocol treatment through 30 days following end of protocol treatment
measure: Overall Survival (OS) in HGG
timeFrame: Day 1 of treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
measure: Progression-Free Survival in HGG
timeFrame: 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
measure: Associations between genomic tumor alterations with radiographic response
timeFrame: From diagnosis through the end of follow-up period.
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Perth
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Toronto
country: Canada
facility: The Hospital for Sick Children (SickKids)
state: Ontario
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Heidelberg
country: Germany
facility: Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
state: Baden-Württemberg
city: Utrecht
country: Netherlands
facility: Princess Máxima Center
Study officials:
affiliation: Children's Hospital of Michigan
name: Hamza Gorsi, MD
role: STUDY_CHAIR
affiliation: Dana-Farber Cancer Institute
name: Susan Chi, MD
role: STUDY_CHAIR
affiliation: Nationwide Children's Hospital
name: Maryam Fouladi, MD
role: PRINCIPAL_INVESTIGATOR
References: