Clinical Trials Logo

Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT06333899
Other study ID # CONNECT2111
Secondary ID
Status Not yet recruiting
Phase Early Phase 1
First received
Last updated
Start date September 1, 2024
Est. completion date September 1, 2034

Study information

Verified date March 2024
Source Nationwide Children's Hospital
Contact Leonie Mikael, PhD
Phone 16147223284
Email LEONIE.MIKAEL@NATIONWIDECHILDRENS.ORG
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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) 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. 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. 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 will start at the recommended phase 2 dose of 115 mg/m2/day, 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.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 15
Est. completion date September 1, 2034
Est. primary completion date September 1, 2027
Accepts healthy volunteers Accepts Healthy Volunteers
Gender All
Age group 1 Year to 21 Years
Eligibility 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 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 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 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


Intervention

Drug:
Lorlatinib
Continue maintenance monotherapy for total 12 cycles
Lorlatinib with chemotherapy1
Continue lorlatinib with BABY-POG chemotherapy backbone for 72 weeks
Lorlatinib with chemotherapy 2
Continue lorlatinib with HIT-SKK chemotherapy backbone for 42 weeks
Lorlatinib post Radiation
Continue lorlatinib monotherapy 28 days post completion of radiation therapy for 12 cycles

Locations

Country Name City State
Australia Perth Children's Hospital Perth Western Australia
Australia Sydney Children's Hospital Randwick New South Wales
Australia Queensland Children's Hospital South Brisbane Queensland
Canada Montreal Children's Hospital Montréal Quebec
Canada The Hospital for Sick Children (SickKids) Toronto Ontario
Germany Hopp Children's Cancer Center at NCT Heidelberg (KiTZ) Heidelberg Baden-Württemberg
Netherlands Princess Máxima Center Utrecht
United States Children's Hospital Colorado Aurora Colorado
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Ann & Robert H. Lurie Children's Hospital of Chicago Chicago Illinois
United States Cincinnati Children's Hospital Medical Center Cincinnati Ohio
United States Nationwide Children's Hospital Columbus Ohio
United States Duke University Health System Durham North Carolina
United States Texas Children's Hospital Houston Texas
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States Seattle Children's Hospital Seattle Washington
United States Children's National Medical Center Washington District of Columbia

Sponsors (2)

Lead Sponsor Collaborator
Nationwide Children's Hospital Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Germany,  Netherlands, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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. from date on treatment until the end of cycle 2 (each cycle is 28 days)
Primary 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 Objective Response Rate (ORR) in HGG 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. From Day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary Overall Survival (OS) in HGG 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. From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
Secondary Progression-Free Survival in HGG 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. 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
See also
  Status Clinical Trial Phase
Recruiting NCT05664243 - A Phase 1b / 2 Drug Resistant Immunotherapy With Activated, Gene Modified Allogeneic or Autologous γδ T Cells (DeltEx) in Combination With Maintenance Temozolomide in Subjects With Recurrent or Newly Diagnosed Glioblastoma Phase 1/Phase 2
Completed NCT02768389 - Feasibility Trial of the Modified Atkins Diet and Bevacizumab for Recurrent Glioblastoma Early Phase 1
Recruiting NCT05635734 - Azeliragon and Chemoradiotherapy in Newly Diagnosed Glioblastoma Phase 1/Phase 2
Completed NCT03679754 - Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma, a Substudy to ATI001-102 Phase 1
Completed NCT01250470 - Vaccine Therapy and Sargramostim in Treating Patients With Malignant Glioma Phase 1
Terminated NCT03927222 - Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma Phase 2
Recruiting NCT03897491 - PD L 506 for Stereotactic Interstitial Photodynamic Therapy of Newly Diagnosed Supratentorial IDH Wild-type Glioblastoma Phase 2
Active, not recruiting NCT03587038 - OKN-007 in Combination With Adjuvant Temozolomide Chemoradiotherapy for Newly Diagnosed Glioblastoma Phase 1
Completed NCT01922076 - Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas Phase 1
Recruiting NCT04391062 - Dose Finding for Intraoperative Photodynamic Therapy of Glioblastoma Phase 2
Active, not recruiting NCT03661723 - Pembrolizumab and Reirradiation in Bevacizumab Naïve and Bevacizumab Resistant Recurrent Glioblastoma Phase 2
Active, not recruiting NCT02655601 - Trial of Newly Diagnosed High Grade Glioma Treated With Concurrent Radiation Therapy, Temozolomide and BMX-001 Phase 2
Completed NCT02206230 - Trial of Hypofractionated Radiation Therapy for Glioblastoma Phase 2
Completed NCT03493932 - Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade Phase 1
Terminated NCT02709889 - Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors Phase 1/Phase 2
Recruiting NCT06058988 - Trastuzumab Deruxtecan (T-DXd) for People With Brain Cancer Phase 2
Completed NCT03018288 - Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM) Phase 2
Withdrawn NCT03980249 - Anti-Cancer Effects of Carvedilol With Standard Treatment in Glioblastoma and Response of Peripheral Glioma Circulating Tumor Cells Early Phase 1
Not yet recruiting NCT04552977 - A Trail of Fluzoparil in Combination With Temozolomide in Patients With Recurrent Glioblastoma Phase 2
Withdrawn NCT02876003 - Efficacy and Safety of G-202 in PSMA-Positive Glioblastoma Phase 2