Lorlatinib for the Treatment of Children with Newly Diagnosed High-Grade Gliomas with ROS1 and ALK Fusion Alterations, TarGeT-L Trial

Status: active

This phase II trial tests the effect of lorlatinib alone and in combination with standard chemotherapy, such as vincristine, cyclophosphamide, cisplatin, etoposide, methotrexate, and carboplatin, or after radiation therapy in treating children with newly diagnosed high-grade gliomas with ROS1 and ALK fusion alterations. Lorlatinib blocks certain proteins made by the ALK gene. Blocking these proteins may stop the growth and spread of tumor cells. Lorlatinib is a type of tyrosine kinase inhibitor. Vincristine is in a class of medications called vinca alkaloids. It works by stopping tumor cells from growing and dividing and may kill them. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell’s deoxyribonucleic acid (DNA) and may kill tumor cells. It may also lower the body’s immune response. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells. Methotrexate is in a class of medications called antimetabolites. It is also a type of antifolate. Methotrexate stops cells from using folic acid to make DNA and may kill tumor cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Radiation therapy (RT) uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. 3-dimensional (D) conformal RT uses a computer to create a 3-D picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. Intensity-modulated radiation therapy (IMRT) is a type of 3-D RT that uses computer-generated images to show the size and shape of the tumor. Then beams of radiation of different intensities are aimed at the tumor from many angles. This type of RT reduces the damage to healthy tissue near the tumor. Giving lorlatinib may be safe, tolerable, and/or effective alone and in combination with standard chemotherapy or after RT in treating patients with newly diagnosed ALK or ROS1 fusion alteration positive high-grade gliomas.

Inclusion Criteria

Patients must be ≥ 12 months and ≤ 21 years of age at the time of study enrollment on Targeted Pediatric High-Grade Glioma Therapy Screening Study (TarGeT-SCR)
Patients with newly diagnosed high-grade glioma (HGG), including diffuse intrinsic pontine gliomas (DIPG), whose tumors harbor an ALK or ROS1 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 World Health Organization (WHO) grade 2-4 glioma * All other HGGs must be grade 3 or 4
Patients must begin study treatment within 42 days from date of diagnosis and/or definitive surgery, whichever is later
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 ROS1 fusion, must be discussed with the study chair on a case-by-case basis
Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age. 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
Patients must not have received any prior anti-cancer chemotherapy
Prior use of corticosteroids is allowed
Peripheral absolute neutrophil count (ANC) ≥ 1000/uL
Platelet count ≥ 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
Hemoglobin > 8 g/dL (may receive transfusions)
Serum creatinine within normal institutional limits OR * Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70ml/min/1.73 m^2
Total bilirubin ≤ 2.5 x institutional upper limit of normal
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal
Pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest)
Corrected QT interval (QTc) ≤ 470 msec (by Bazett formula)
Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
All patients and/or their parents or legally authorized representatives must sign a written informed consent and assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria

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
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
Patients who have received prior solid organ transplantation are not eligible
Patients must not have malabsorption syndrome or other condition affecting oral absorption
Patients must not be receiving any treatment with a strong cytochrome P450 3A4 (CYP3A4/5) inhibitor or inducer. Discontinue strong CYP3A4/5 inducers for 3 plasma half-lives of the strong CYP3A inducer prior to treatment with lorlatinib. Moderate inducers of CYP3A4 should be avoided
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
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
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
Patients with a known personal history of acute or chronic severe psychiatric disorders or current history of suicidal ideation and history of suicide attempt

Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT06333899.

United States

Ohio

Cincinnati

Cincinnati Children's Hospital Medical Center

Status: Active

Contact: Peter Matthew Kennedy de Blank

Phone: 513-517-2068

Email: peter.deblank@cchmc.org

Columbus

Nationwide Children's Hospital

Status: Active

Contact: Maryam Fouladi

Phone: 614-722-5758

Email: Maryam.Fouladi@nationwidechildrens.org

PRIMARY OBJECTIVES:

I. 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.

II. To assess the feasibility and safety of lorlatinib when given in combination with chemotherapy in young children with newly diagnosed high-grade glioma with ALK or ROS fusion, and the safety of lorlatinib when given post-focal radiation therapy.

SECONDARY OBJECTIVES:

I. 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.

II. To assess overall (OS) and progression-free survivals (PFS) of children with high-grade gliomas treated with a lorlatinib-containing regimen at 1, 3 and 5 years and compared to historical data from Baby Pediatric Oncology Group (BABYPOG) and HIT-SKK.

III. Explore longitudinal associations of genomic, transcriptomic, epigenetic, and/or immunologic alterations of tumor at diagnosis, recurrence, or autopsy with radiographic response and advanced neuro-imaging measures.

EXPLORATORY OBJECTIVES:

I. To biologically characterize tumors and to assess biomarker of tumor response or resistance by next generation sequencing methods such as methylation profiling, whole genome sequencing (WGS) or whole exome sequencing (WES) (tumor and blood), and ribonucleic acid sequencing (RNA-Seq) (tumor).

II. To explore the ability of lorlatinib to inhibit ALK- or ROS1-mediated signaling in tumor when available ( e.g at progression).

III. To explore volumetric measurements of tumor including necrotic and cystic components (if present) and to correlate with 2-dimensional measurements and response criteria.

IV. To evaluate feasibility and reliability of peripheral blood and/or cerebrospinal fluid (CSF)-based liquid biopsy as minimally-invasive measures of response or early detection of recurrence.

V. To assess myeloid cell signatures and immune, mutational, and gene expression profiles that potentiate high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG) progress and/or predict response.

VI. To analyze volumetric measures of tumor radiographic response, both manually segmented, semi-automated programs as well as automated artificial intelligence software, and correlate results with outcomes.

OUTLINE:

Patients receive lorlatinib orally (PO) or via nasogastic (NG), or gastric (G) tube once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 2 arms based on response.

ARM I (CR OR CCR): After 2 cycles, patients with CR or CCR, continue to receive lorlatinib for up to a total of 12 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 12 cycles for up to a maximum of 26 cycles if they are receiving clinical benefit.

ARM II (PR OR SD): Patients are assigned to 1 of 2 arms based on age.

ARM IIA (PATIENTS ≤ 48 MONTHS): After cycle 2, patients with PR or SD may receive lorlatinib PO or via NG or G tube QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also receive 1 of the 2 following standard chemotherapy regimens per investigator choice.

REGIMEN I (BABYPOG): Each course of this regimen consists of 3 cycles (A, A2, and B) administered consecutively at 28 day intervals.

CYCLE A (WEEKS 1, 13, 25, 37, 49, AND 61): Patients receive vincristine intravenously (IV) over 15 minutes on days 1, 15, and 22 and cyclophosphamide IV over 30 minutes on day 1 of each 28 day cycle.

CYCLE A2 (WEEKS 5, 17, 29, 41, 53, AND 65): Patients receive vincristine IV over 15 minutes on days 1 and 8 and cyclophosphamide IV over 30 minutes on day 1 of each 28 day cycle.

CYCLE B (WEEKS 9, 21, 33, 45, 57 AND 69): Patients receive cisplatin IV over 6 hours on day 1 and etoposide IV over 1 hour on days 3 and 4 of each 28 day cycle.

Courses repeat every 12 weeks for up to 6 courses (72 weeks) in the absence of disease progression.

REGIMEN II (HIT-SKK): Each course consists of 4 elements (cycles) administered consecutively at 2-3 week intervals.

ELEMENT IIS (WEEKS 1, 10, 19, 28, AND 34): Patients receive cyclophosphamide IV over 1 hour on days 1-3 and vincristine on day 1 of each cycle.

ELEMENT IIIS/1 (WEEKS 3, 12, AND 21): Patients receive methotrexate IV over 24 hours and vincristine IV on day 1 of each cycle.

ELEMENT IIIS/2 (WEEKS 5, 14, AND 23): Patients receive methotrexate IV over 24 hours and vincristine IV on day 1 of each cycle.

ELEMENT IVS (WEEKS 7, 16, 25, 31, AND 37): Patients receive carboplatin IV over 1 hour and etoposide IV over .5 hour on days 1-3 of each cycle.

Courses repeat 3 times in the absence of disease progression or unacceptable toxicity. Then elements IIS and IVS repeat twice in the absence of disease progression or unacceptable toxicity.

ARM IIB (PATIENTS > 48 MONTHS): After 2 cycles, patients with PR or SD may undergo standard 3D-conformal or IMRT QD Monday-Friday for 33 fractions over up to 6-7 weeks. After completion of RT, patients then receive lorlatinib PO or via NG or G tube QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 12 cycles. Patients may continue to receive treatment beyond 12 cycles for up to a maximum 26 cycles if they are receiving clinical benefit.

Additionally, patients undergo magnetic resonance imaging (MRI), blood sample collection and lumbar puncture (as clinically indicated) throughout the study.

After completion of study treatment, patients are followed up at 30 days then every 6 months for up to 7 years.

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Lorlatinib for the Treatment of Children with Newly Diagnosed High-Grade Gliomas with ROS1 and ALK Fusion Alterations, TarGeT-L Trial

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