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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT06333899
Registration number
NCT06333899
Ethics application status
Date submitted
14/03/2024
Date registered
27/03/2024
Date last updated
27/03/2024
Titles & IDs
Public title
Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion
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Scientific 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
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Secondary ID [1]
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CONNECT2111
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
High Grade Glioma
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Diffuse Intrinsic Pontine Glioma
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Anaplastic Astrocytoma
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Infant Type Hemispheric Glioma
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Glioblastoma
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Glioblastoma Multiforme
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WHO Grade III Glioma
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WHO Grade IV Glioma
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Diffuse Midline Glioma, H3K27-altered
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Condition category
Condition code
Cancer
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Brain
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Cancer
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Children's - Brain
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Lorlatinib
Treatment: Drugs - Lorlatinib with chemotherapy1
Treatment: Drugs - Lorlatinib with chemotherapy 2
Treatment: Drugs - Lorlatinib post Radiation
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.
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
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.
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
Treatment: Drugs: Lorlatinib
Continue maintenance monotherapy for total 12 cycles
Treatment: Drugs: Lorlatinib with chemotherapy1
Continue lorlatinib with BABY-POG chemotherapy backbone for 72 weeks
Treatment: Drugs: Lorlatinib with chemotherapy 2
Continue lorlatinib with HIT-SKK chemotherapy backbone for 42 weeks
Treatment: Drugs: Lorlatinib post Radiation
Continue lorlatinib monotherapy 28 days post completion of radiation therapy for 12 cycles
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Disease Control Rate
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Assessment method [1]
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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.
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Timepoint [1]
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from date on treatment until the end of cycle 2 (each cycle is 28 days)
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Primary outcome [2]
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Number of participants with lorlatinib-related adverse events as assessed by CTCAE v5.0
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Assessment method [2]
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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
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Timepoint [2]
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From Day 1 of protocol treatment through 30 days following end of protocol treatment
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Secondary outcome [1]
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Objective Response Rate (ORR) in HGG
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Assessment method [1]
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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.
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Timepoint [1]
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From Day 1 of protocol treatment through 30 days following end of protocol treatment
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Secondary outcome [2]
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Overall Survival (OS) in HGG
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Assessment method [2]
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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.
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Timepoint [2]
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From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
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Secondary outcome [3]
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Progression-Free Survival in HGG
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Assessment method [3]
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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.
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Timepoint [3]
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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
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Eligibility
Key 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
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Minimum age
1
Year
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Maximum age
21
Years
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Sex
Both males and females
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Can healthy volunteers participate?
Yes
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Key exclusion criteria
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
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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 0
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Not yet recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
1/09/2024
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Actual
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
1/09/2034
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Actual
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Sample size
Target
15
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
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Recruitment hospital [1]
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Sydney Children's Hospital - Randwick
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Recruitment hospital [2]
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Queensland Children's Hospital - South Brisbane
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Recruitment hospital [3]
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Perth Children's Hospital - Perth
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Recruitment postcode(s) [1]
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2031 - Randwick
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Recruitment postcode(s) [2]
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4101 - South Brisbane
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Recruitment postcode(s) [3]
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6000 - Perth
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Colorado
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United States of America
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State/province [2]
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District of Columbia
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United States of America
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State/province [3]
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Illinois
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Country [4]
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United States of America
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State/province [4]
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Massachusetts
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Country [5]
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United States of America
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State/province [5]
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North Carolina
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Country [6]
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Ohio
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Country [7]
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United States of America
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Pennsylvania
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Country [8]
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United States of America
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Texas
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Country [9]
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United States of America
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Washington
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Country [10]
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Canada
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State/province [10]
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Ontario
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Canada
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State/province [11]
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Quebec
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Country [12]
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Germany
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State/province [12]
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Baden-Württemberg
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Country [13]
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Netherlands
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State/province [13]
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Utrecht
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Funding & Sponsors
Primary sponsor type
Other
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Name
Nationwide Children's Hospital
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Pfizer
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Address [1]
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT06333899
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Hamza Gorsi, MD
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Address
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Children's Hospital of Michigan
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Leonie Mikael, PhD
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Address
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Phone
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16147223284
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT06333899
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