INCB7839 in Treating Children With Recurrent/Progressive High-Grade Gliomas
- Conditions
- Glioblastoma MultiformeAnaplastic OligodendrogliomaHigh-grade Astrocytoma NOSAnaplastic AstrocytomaDIPGCNS Primary Tumor, NOS (Malignant Glioma)
- Interventions
- Registration Number
- NCT04295759
- Lead Sponsor
- Pediatric Brain Tumor Consortium
- Brief Summary
This is a multicenter phase 1 trial of INCB7839 for children with recurrent or progressive high-grade gliomas, including, but not limited to, diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs), after upfront therapy.
- Detailed Description
INCB7839 is an inhibitor of the ADAM (A Disintegrin and Metalloprotease) 10 and 17 proteases. Neuronal activity regulates glioma growth through neuroligin-3 (NLGN3). ADAM 10 is the protease responsible for NLGN3 release into the tumor microenvironment and represents a promising therapeutic target.
Pre-clinical studies of INCB7839 in patient-derived pediatric high-grade gliomas (GBM and DIPG) revealed that INCB7839 inhibits pediatric high- grade glioma growth and improves overall survival. In vivo testing also demonstrated that INCB7839 penetrates brain tissue sufficient to achieve its pharmacodynamic effect of ADAM10 inhibition. Further pre-clinical studies in other animals revealed minimal toxicity, including non-adverse to mild increases in serum hepatobiliary enzymes, protein, calcium, cholesterol values, along with minimal decreases in RBC mass parameters; all parameters recovered.
INCB7839 has been evaluated in Phase I and Phase II clinical trials for previously treated solid tumors and breast cancer. Of the adverse events (AEs) noted, the majority were mild-to-moderate in severity, the most frequent being fatigue, nausea, anorexia, diarrhea, emesis, abdominal pain, anemia and constipation. The dose-limiting toxicity for monotherapy with INCB7839 in Phase I clinical trials was declared to be deep venous thrombosis (DVT). Out of 41 patients, there was a total of 9 thrombotic events including mild superficial thrombophlebitis (n=1), DVT (n=4), vena cava thrombosis with renal insufficiency in a patient with squamous cell cancer of the head and neck (n=1), atrial thrombosis in patient with breast cancer (n=1), and pulmonary embolism in patients with hormone-refractory prostate cancer (n=2). Overall, INCB7839 does exhibit a pro-coagulant effect in some adult patients, resulting in an increased incidence of DVT, whether used alone or in combination. The mechanism of this effect is unknown, and there is no clear relationship between the frequency of thrombosis and the dose administered.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 13
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Dose-finding INCB7839 INCB7839 dosing will begin at 120 mg/m2/dose BID which is equivalent to the adult RP2D (200 mg PO BID) based on a typical adult size of 1.67m2. The INCB7839 dose may be decreased to 80 mg/m2/dose BID if the staring dose is not tolerable. 28 consecutive days (4 weeks) will constitute one course. Patients may continue to receive INCB7839 for 26 courses (approximately 2 years).
- Primary Outcome Measures
Name Time Method Number of Patients Who Experienced Dose-limiting Toxicities (DLTs) Approximately 28 days All subjects evaluable for dose-finding were classified as having DLT or not having DLT, and the number of subjects having DLT was reported. Any INCB7839-related adverse events during the first course of treatment that led to dose reduction, permanent cessation of therapy, or a delay in treatment of \>7 days were considered DLTs. Hematologic DLTs included any grade 4 hematologic toxicity except lymphopenia; grade 3 neutropenia with fever; or requiring a platelet transfusion on 2 separate days during a single course. Non-hematologic DLTs included any grade 4 non-hematologic toxicity; any grade 3 non-hematologic toxicities with some exceptions such as grade 3 fever or infection of fewer than 5 days in duration; any grade 2 non-hematologic toxicity persisting for \>7 days and considered medically significant; and any deep venous thrombotic event (superficial phlebitis was excluded unless grade 3 or 4 or unless it met another criteria for DLT).
Maximum Tolerated Dose (MTD) and/or Recommend Phase II Dose (RP2D) of INCB7839 Approximately 28 days A design similar to the Rolling-6 design was used and 6 slots were initially opened on the starting dose level (dose level 1, INCB7839 120 mg/m\^2/dose BID). If no more than one dose-limiting toxicity (DLT) was observed in these 6 subjects, we would expand this cohort to at least 12 patients for additional safety and pharmacokinetic information. If more than 3 DLTs were observed in 12 subjects at dose level 1, then the initially identified maximum tolerated dose based on 6 subjects would be considered unsafe and de-escalation to a lower dose level (INCB7839 80 mg/m\^2/dose BID) would be considered.
Area Under the Curve (AUC) of INCB7839 Up to 3 days after the start of treatment Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected to create the curve were 0, 1, 4, 8, 24 and 48 hours post-dose. The area under the curve (AUC) was estimated using a noncompartmental method.
Maximum Concentration [Cmax] of INCB7839 Up to 3 days after the start of treatment Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected were 0, 1, 4, 8, 24 and 48 hours post-dose. The maximum concentration (Cmax) was estimated using a noncompartmental method.
Apparent Oral Clearance [CL/F] of INCB7839 Up to 3 days after the start of treatment Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected were 0, 1, 4, 8, 24 and 48 hours post-dose. Clearance (CL/F) was estimated using a noncompartmental method.
Time to Reach Maximum Concentration [Tmax] of INCB7839 Up to 3 days after the start of treatment Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected were 0, 1, 4, 8, 24 and 48 hours post-dose. The time to reach maximum concentration (Tmax) was estimated using a noncompartmental method.
- Secondary Outcome Measures
Name Time Method Percent Probability of Progression-free Survival 3 months from first dose of INCB7839 Progression-free survival (PFS) was defined as the time interval from date of treatment start to date of first event (progressive disease or death due to any cause) for patients with events, or to the date of last follow-up for patients without events. PFS was estimated using the method of Kaplan and Meier and reported with a 95% confidence interval. We had planned to report the 2-year PFS estimate, but the 2-year estimate was not defined as most subjects progressed prior to 2 years. The 3-month PFS estimate was reported. All subjects are off study and data collection has concluded for this outcome measure.
Percent Probability of Overall Survival 3 months from first dose of INCB7839 Overall survival (OS) was defined as the time interval from date of treatment initiation to date of death due to any cause or to the date of last follow-up for survivors. OS was estimated using the method of Kaplan and Meier and reported with a 95% confidence interval. All subjects are off study and data collection has concluded for this outcome measure.
Duration of Response Up to 2 years following last dose of INCB7839 Complete or partial responses were considered responses. Response was evaluated by imaging or clinical progression. Duration of response was measured from the time measurement criteria were met for complete or partial response until the first date that recurrent or progressive disease was objectively documented.
Trial Locations
- Locations (11)
Stanford University and Lucile Packard Children's Hospital
🇺🇸Palo Alto, California, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Cincinnati Children Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Children Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States