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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06333899




Registration number
NCT06333899
Ethics application status
Date submitted
14/03/2024
Date registered
27/03/2024

Titles & IDs
Public title
Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion
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
Secondary ID [1] 0 0
CONNECT2111
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High Grade Glioma 0 0
Diffuse Intrinsic Pontine Glioma 0 0
Anaplastic Astrocytoma 0 0
Infant Type Hemispheric Glioma 0 0
Glioblastoma 0 0
Glioblastoma Multiforme 0 0
WHO Grade III Glioma 0 0
WHO Grade IV Glioma 0 0
Diffuse Midline Glioma, H3K27-altered 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Disease Control Rate
Timepoint [1] 0 0
from date on treatment until the end of cycle 2 (each cycle is 28 days)
Primary outcome [2] 0 0
Number of participants with lorlatinib-related adverse events as assessed by CTCAE v5.0
Timepoint [2] 0 0
From Day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary outcome [1] 0 0
Objective Response Rate (ORR) in HGG
Timepoint [1] 0 0
From Day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary outcome [2] 0 0
Overall Survival (OS) in HGG
Timepoint [2] 0 0
From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
Secondary outcome [3] 0 0
Progression-Free Survival in HGG
Timepoint [3] 0 0
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

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
Minimum age
1 Year
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 0
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
1/09/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/09/2034
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Washington
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Canada
State/province [11] 0 0
Quebec
Country [12] 0 0
Germany
State/province [12] 0 0
Baden-Württemberg
Country [13] 0 0
Netherlands
State/province [13] 0 0
Utrecht

Funding & Sponsors
Primary sponsor type
Other
Name
Nationwide Children's Hospital
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Pfizer
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Hamza Gorsi, MD
Address 0 0
Children's Hospital of Michigan
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Leonie Mikael, PhD
Address 0 0
Country 0 0
Phone 0 0
16147223284
Fax 0 0
Email 0 0
LEONIE.MIKAEL@NATIONWIDECHILDRENS.ORG
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT06333899