A Phase 1 interventional study of APX005M treatment for recurrent or refractory primary malignant CNS tumor patients and APX005M treatment for newly diagnosed DIPG patients in Glioblastoma Multiforme, High-grade Astrocytoma Not Otherwise Specified (NOS) and CNS Primary Tumor, Not Otherwise Specified (NOS), sponsored by Pediatric Brain Tumor Consortium. Completed at 11 sites in United States. Open to participants aged 1 Year to 21 Years. Per ClinicalTrials.gov, last updated 2026-08-13.
Sponsored by Pediatric Brain Tumor Consortium · Phase 1, Interventional, and Treatment
This phase I trial studies the side effects and best dose of APX005M in treating younger patients with primary malignant central nervous system tumor that is growing, spreading, or getting worse (progressive), or newly diagnosed diffuse intrinsic pontine glioma. APX005M can trigger activation of B cells, monocytes, and dendritic cells and stimulate cytokine release from lymphocytes and monocytes. APX005M can mediate a direct cytotoxic effect on CD40+ tumor cells.
This is a multicenter phase I trial of APX005M in patients with recurrent or refractory primary malignant central nervous system tumor, or newly diagnosed diffuse intrinsic pontine glioma.
APX005M is a humanized IgG1κ mAb that binds to CD40. APX005M binds to both human and cynomolgus monkey CD40 with high affinity, triggering activation of B cells, monocytes, and dendritic cells and stimulating cytokine release from both human and monkey lymphocytes and monocytes. APX005M does not bind to mouse or rat CD40. CD40 is also expressed on many human tumor cells, and APX005M can mediate a direct cytotoxic effect on CD40+ tumor cells.
Activation of CD40 on tumor cells results in tumor cell apoptosis and inhibition of tumor growth. CD40 agonistic antibodies have demonstrated potent antitumor immune response stimulation in both animal models and cancer patients. Due to its action on both immune and tumor cells, CD40 has been studied as a target for novel cancer immunotherapy.
Apexigen has declared the adult recommended phase 2 dose to be 0.3 mg/kg because no dose limiting toxicities were encountered at that dose and the pharmacodynamic profile was similar to the 1 mg/kg maximally tolerated dose. This phase 1 clinical trial is to study APX005M in children with central nervous system tumors.
Stratum 2: Newly diagnosed DIPG patients (on-hold until pediatric RP2D has been established in Stratum 1) Patients with diffuse intrinsic pontine gliomas (DIPGs) will be eligible 6 to 14 weeks post-completion of radiation therapy if they do not have any evidence of progression. Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation. Patients with pontine tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors have been biopsied and (1) are proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma or fibrillary astrocytoma or (2) have a histone mutation typically seen in DIPG. Patients with disseminated disease are not eligible, and MRI of spine must be performed if disseminated disease is suspected by the treating physician.
Stratum 2: Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility.
Refractory/Recurrent patients Patients must have recovered from the acute treatment related toxicities (defined as \< grade 1) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study.
Myelosuppressive chemotherapy -- Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea.
Biological agent: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the biologic agent ≥ 7 days prior to study enrollment.
For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
Monoclonal antibody treatment and agents with known prolonged half-lives: At least three half-lives must have elapsed prior to enrollment.
Radiation --
Patients must have had their last fraction of:
Craniospinal irradiation (>24Gy) or total body irradiation or radiation to greater than 50% of pelvis > 3 months prior to enrollment.
Focal irradiation >6 weeks prior to enrollment Local palliative irradiation (small port) ≥4 weeks
Autologous Stem Cell Transplant -- Patient must be ≥ 6 months since autologous bone marrow/stem cell transplant prior to enrollment and have CD4 counts above 200/mm3.
Surgery -- Patients must be at least 4 weeks (28 days) from major surgery and fully recovered from all acute effects of prior surgical intervention.
Patients with seizure disorders may be enrolled if seizures are well controlled.
Patients must have adequate organ and bone marrow function as defined below:
Absolute Neutrophil Count (ANC) ≥ 1.0 x 109 cells/ L Platelets ≥ 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 7 days) Hemoglobin ≥ 8 g/dL (may receive transfusions) Total bilirubin ≤1.5 times institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 3 x institutional upper limit of normal (ULN) Albumin ≥ 3 g/dl Serum creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24 hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.
Age Maximum Serum Creatinine (mg/dL) 1 to \< 2 years 0.6, 0.6 (M, F); 2 to \< 6 years 0.8, 0.8 (M, F); 6 to \< 10 years 1, 1 (M, F); 10 to \< 13 years 1.2, 1.2 (M, F); 13 to \< 16 years 1.5, 1.4 (M, F); ≥ 16 years 1.7, 1.4 (M, F).
Exclusion Criteria:
Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient's first malignancy has been in remission for at least 5 years from the end of treatment.
Patients requiring systemic treatment with either corticosteroids (greater than physiologic replacement, defined as dexamethasone 0.75 mg/m2/day) or other immunosuppressive medications within 14 days of study drug administration will be excluded. However, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Please see section 5.3 for a list of acceptable and unacceptable concomitant medications as well as reporting requirements.
Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as:
Tumor with any evidence of uncal herniation or midline shift Tumor that in the opinion of the site investigator, shows significant mass effect
The recurrent, progressive, or refractory primary malignant non-brainstem CNS tumor patients will be treated with APX005M.
Biological: APX005M treatment for recurrent or refractory primary malignant CNS tumor patients
The newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) patients will be treated with APX005M.
Biological: APX005M treatment for newly diagnosed DIPG patients
APX005M dosing will begin at 0.1 mg/kg, the APX005M dose may be increased (0.3, 0.45, 0.6 mg/kg) or decreased (0.03 mg/kg) in subsequent cohorts until the maximum tolerated dose (MTD) is reached or until dose level 3 (0.6 mg/kg) is complete without the MTD being defined. APX005M will be administered at the assigned dose level every 21 days (3 weeks). Patients may continue to receive APX005M for 36 courses (approximately 2 years) or until disease progression, unacceptable toxicity or death, whichever occurs first.
The starting dose of APX005M for the DIPG patients will be one dose level below the recommended phase II dose (RP2D) determined in Stratum 1 patients. The dose may be decreased or increased to the RP2D established in Stratum 1. APX005M will be administered at the assigned dose level every 21 days (3 weeks). Patients may continue to receive APX005M for 36 courses (approximately 2 years) or until disease progression, unacceptable toxicity or death, whichever occurs first.
Number of Patients Who Experienced Dose-limiting Toxicities (DLTs)
DLTs were defined as adverse events (AE) at least possibly attributed to APX005M that occurred during the first 2 courses (6 weeks) following APX005M administration. DLTs included any APX005M-related AE that led to dose reduction or permanent cessation of therapy or resulted in a treatment delay \>2 weeks. Hematologic DLTs included grade 3 neutropenia with fever, any grade 4 hematologic toxicity except lymphopenia, and grade 3 thrombocytopenia on 2 separate days or requiring platelet transfusion on 2 days within a 7-day period. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, grade 3 or higher cytokine release syndrome, or any grade 3 non-hematologic toxicity with some exceptions such as grade 3 nausea/vomiting \<5 days or grade 3 diarrhea that responded to treatment within 5 days.
Time frame: 6 weeks
Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) of APX005M in Stratum 1
Based on the 3+3 design, the MTD of APX005M was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT, and the next higher dose level was determined to be too toxic. A total of 12 subjects were to be treated at the MTD/RP2D to further define the toxicity profile. Stratum 1 consisted of patients with recurrent or refractory primary malignant central nervous system tumors.
Time frame: 6 weeks (first 2 courses of treatment)
Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) of APX005M in Stratum 2
The starting dose level for Stratum 2 was one dose level below the RP2D determined in Stratum 1. If there were no dose-limiting toxicities in the first 3 patients enrolled on Stratum 2, then we escalated to the Stratum 1 RP2D and could treat 6 diffuse intrinsic pontine glioma (DIPG) patients simultaneously. The RP2D was defined as the dose level at which 6 patients were treated with no more than one dose-limiting toxicity. Stratum 2 patients were those with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
Time frame: 6 weeks (first 2 courses of treatment)
Serum Concentration of APX005M
Serial blood samples for APX005M pharmacokinetic studies were collected during courses 1 and 2 at pre-dose, at the end of infusion, and at 4, 24 ± 1 (day 2), and 168 ± 4 hours (day 8) from the start of infusion in that course. During courses 3 and 4, samples were obtained pre-dose and end of induction. Serum concentrations of sotigalimab were measured using a validated electrochemiluminescent (ECL) immunoassay (Method ICD 853 v1.00). Mean serum concentrations with standard deviations were calculated using Phoenix® WinNonlin® v.8.4. Concentrations below the limit of quantitation (0.010 μg/mL) were replaced with 0 to calculate means and SDs.
Time frame: Up to 12 weeks from start of study drug
Overall Survival for Stratum 2 (DIPG) Patients
Overall survival was defined as the time interval from treatment initiation to death from any cause or to date of last follow-up for survivors. Survival was estimated using the method of Kaplan and Meier. The 1-year estimate of survival is reported with a 95% confidence interval; estimates are reported by dose level. Stratum 2 patients were those with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
Time frame: 1 year
Progression-free Survival for Stratum 2 (DIPG) Patients
Progression-free survival (PFS) was defined as the time interval from treatment initiation to date of first event (relapsed or progressive disease based on imaging or clinical progression or death from any cause) or to the date of last follow-up for patients without events. PFS was estimated using the method of Kaplan and Meier. The 1-year estimate of PFS is reported with a 95% confidence interval. PFS estimates were reported separately by dose level. Stratum 2 patients were those with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
Time frame: 1 year
Overall Response Rate for Stratum 2 (DIPG) Patients
Complete or partial responses were considered responses. Response was evaluated by imaging or clinical progression. The response rate (percentage of participants with responses) is reported with a 95% Blyth-Still-Casella confidence interval. Response rates are reported separately by dose level.
Time frame: Up to 2 years
Duration of Response for Stratum 2 (DIPG) Patients
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 are met for complete or partial response until the first date that recurrent or progressive disease was objectively documented.
Time frame: Up to 2 years
Progression-free Survival for Stratum 1 (Recurrent/Refractory) Patients
Progression-free survival (PFS) was defined as the time interval from treatment initiation to date of first event (relapsed or progressive disease based on imaging or clinical progression or death from any cause) or to the date of last follow-up for patients without events. PFS was estimated using the method of Kaplan and Meier. The 1-year estimate of PFS is reported with a 95% confidence interval. PFS estimates were reported separately by dose level. Stratum 1 patients were those with recurrent or refractory primary malignant CNS tumors.
Time frame: 1 year
Incidence of Anti-APX005M Antibodies
Serial blood samples for anti-drug-antibodies (ADA) were to be collected prior to dosing on courses 1, 2, 3, and 4, then every third course (courses 7 and 10), and then every 4 courses (courses 14, 18, 22, 26, 30, 34) until the end of therapy visit and collected into serum tubes. Percentages of patients with positive anti-drug antibodies with a 95% Blyth-Still-Casella confidence interval are reported by time point.
Time frame: Prior to dosing on courses 1, 2, 3, 4, 7, 10, 14, 18, 22, 26, 30, and 34 and at the end of therapy (up to end of course 36)
Concentration of the Cytokine Tumor Necrosis Factor-alpha (TNF-alpha)
The cytokine was quantitated using V-PLEX Human Proinflammatory Panel, a multiplex immunoassay kit developed by Meso Scale Diagnostics (MSD). A four-parameter logistic fit calibration curve was generated and used to calculate concentrations in tested samples. Analyses were performed at pre-treatment and 1 week following the first dose of drug and additionally at 2, 3, 6, and 9 weeks following the course 1 drug dose if feasible. The mean concentration of TNF-alpha in pg/ml was reported with a standard deviation. When only one patient was analyzed, the standard deviation was reported as 0 (rather than undefined).
Time frame: Pre-treatment (week 0), 1 week, 2 week, 3 weeks, 6 weeks and 9 weeks post-treatment
Concentration of the Cytokine Interleukin-8 (IL-8)
The cytokine was quantitated using V-PLEX Human Proinflammatory Panel, a multiplex immunoassay kit developed by Meso Scale Diagnostics (MSD). A four-parameter logistic fit calibration curve was generated and used to calculate concentrations in tested samples. Analyses were performed at pre-treatment and 1 week following the first dose of drug and additionally at 2, 3, 6, and 9 weeks following the course 1 drug dose if feasible. The mean concentration of IL-8 in pg/ml was reported with a standard deviation. When only 1 participant analyzed, the standard deviation was reported as 0 (rather than undefined).
Time frame: Pre-treatment (week 0), 1 week, 2 week, 3 weeks, 6 weeks and 9 weeks post-treatment
Tumor Mutation Burden Based on Whole Exome Sequencing of Tumor Tissue
Tumor mutation burden was defined as the number of somatic mutations per megabase. Average tumor mutation burden was reported with a standard deviation. When only one patient was analyzed, the standard deviation was reported as 0 rather than undefined.
Time frame: Day 0 of treatment
Tumor Mutation Burden Based on RNA Sequencing of Tumor Tissue
Tumor mutation burden was defined as the number of somatic mutations per megabase. Average tumor mutation burden was reported with a standard deviation. When only one patient was analyzed, the standard deviation was reported as 0 rather than undefined.
Time frame: Day 0 of treatment
Mutation Burden Based on TCR Sequencing
Mutation burden as detected by comparing the TCR sequencing of tumor tissue and/or PBMC. Mean numbers of clonotypes were reported by time point with standard deviations.
Time frame: Day 0 and Days 7, 14, and 21 after the start of treatment
Patients ≥1 and ≤21 years of age with recurrent or refractory primary malignant central nervous system (CNS) tumors (Stratum 1) or newly diagnosed diffuse intrinsic pontine glioma (DIPG) (Stratum 2) were enrolled at Pediatric Brain Tumor Consortium (PBTC) member institutions. The first patient was enrolled on 3/1/2018 and the last patient was enrolled on 1/20/2023. Accrual was closed after the maximum tolerated dose/recommended phase II dose was determined for both strata.
| Milestone | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Started | 3 | 3 | 15 | 6 | 5 |
| Completed | 0 | 0 | 0 | 0 | 0 |
| Not completed | 3 | 3 | 15 | 6 | 5 |
| Withdrew: Lack of efficacy | 3 | 3 | 13 | 6 | 1 |
| Withdrew: Adverse event | 0 | 0 | 1 | 0 | 4 |
| Withdrew: Subject deemed ineligible after enrollment | 0 | 0 | 1 | 0 | 0 |
DLTs were defined as adverse events (AE) at least possibly attributed to APX005M that occurred during the first 2 courses (6 weeks) following APX005M administration. DLTs included any APX005M-related AE that led to dose reduction or permanent cessation of therapy or resulted in a treatment delay \>2 weeks. Hematologic DLTs included grade 3 neutropenia with fever, any grade 4 hematologic toxicity except lymphopenia, and grade 3 thrombocytopenia on 2 separate days or requiring platelet transfusion on 2 days within a 7-day period. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, grade 3 or higher cytokine release syndrome, or any grade 3 non-hematologic toxicity with some exceptions such as grade 3 nausea/vomiting \<5 days or grade 3 diarrhea that responded to treatment within 5 days.
| Participants | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Number of Patients Who Experienced Dose-limiting Toxicities (DLTs) | 0 | 0 | 2 | 0 | 3 |
Based on the 3+3 design, the MTD of APX005M was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT, and the next higher dose level was determined to be too toxic. A total of 12 subjects were to be treated at the MTD/RP2D to further define the toxicity profile. Stratum 1 consisted of patients with recurrent or refractory primary malignant central nervous system tumors.
| mg/kg | Stratum 1 |
|---|---|
| Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) of APX005M in Stratum 1 | 0.6 |
The starting dose level for Stratum 2 was one dose level below the RP2D determined in Stratum 1. If there were no dose-limiting toxicities in the first 3 patients enrolled on Stratum 2, then we escalated to the Stratum 1 RP2D and could treat 6 diffuse intrinsic pontine glioma (DIPG) patients simultaneously. The RP2D was defined as the dose level at which 6 patients were treated with no more than one dose-limiting toxicity. Stratum 2 patients were those with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
| mg/kg | Stratum 2 |
|---|---|
| Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) of APX005M in Stratum 2 | 0.3 |
Serial blood samples for APX005M pharmacokinetic studies were collected during courses 1 and 2 at pre-dose, at the end of infusion, and at 4, 24 ± 1 (day 2), and 168 ± 4 hours (day 8) from the start of infusion in that course. During courses 3 and 4, samples were obtained pre-dose and end of induction. Serum concentrations of sotigalimab were measured using a validated electrochemiluminescent (ECL) immunoassay (Method ICD 853 v1.00). Mean serum concentrations with standard deviations were calculated using Phoenix® WinNonlin® v.8.4. Concentrations below the limit of quantitation (0.010 μg/mL) were replaced with 0 to calculate means and SDs.
| μg/mL | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Course 1, pre-dose | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
| Course 1, 1 hour | 0.120 ± 0.115 | 3.95 ± 0.526 | 9.15 ± 2.98 | 3.49 ± 0.984 | 9.87 ± 1.95 |
| Course 1, 4 hours | 0.0357 ± 0 | 2.29 ± 0.349 | 6.64 ± 1.93 | 2.12 ± 1.06 | 7.88 ± 0.280 |
| Course 1, 24 hours | 0 ± 0 | 0 ± 0 | 0.851 ± 1.44 | 0 ± 0 | 0.0136 ± 0.0137 |
| Course 1, 168 hours | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
| Course 2, pre-dose | 0 ± 0 | 1.26 ± 2.19 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
| Course 2, 1 hour | 0.148 ± 0.135 | 4.10 ± 0.247 | 8.47 ± 2.27 | 3.23 ± 1.48 | 9.63 ± 2.22 |
| Course 2, 4 hours | 0.032 ± 0.0253 | 2.66 ± 0.140 | 6.13 ± 1.87 | 1.55 ± 0.959 | 7.41 ± 3.15 |
| Course 2, 24 hours | 0 ± 0 | 0 ± 0 | 0.593 ± 0.872 | 0 ± 0 | 0.0317 ± 0.0448 |
| Course 2, 168 hours | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
| Course 3, pre-dose | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
| Course 3, 1 hour | 0.198 ± 0 | 3.54 ± 0.721 | 7.33 ± 1.98 | 1.89 ± 1 | 9.53 ± 1.80 |
| Course 4, pre-dose | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
| Course 4, 1 hour | 0.0114 ± 0 | 3.98 ± 0 | 8.82 ± 3.11 | 1.26 ± 1.17 | 1.84 ± 0 |
Overall survival was defined as the time interval from treatment initiation to death from any cause or to date of last follow-up for survivors. Survival was estimated using the method of Kaplan and Meier. The 1-year estimate of survival is reported with a 95% confidence interval; estimates are reported by dose level. Stratum 2 patients were those with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
| Percent probability | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|
| Overall Survival for Stratum 2 (DIPG) Patients | 40.0 (4.9 to 75.1) | 25.0 (0.0 to 55.0) |
Progression-free survival (PFS) was defined as the time interval from treatment initiation to date of first event (relapsed or progressive disease based on imaging or clinical progression or death from any cause) or to the date of last follow-up for patients without events. PFS was estimated using the method of Kaplan and Meier. The 1-year estimate of PFS is reported with a 95% confidence interval. PFS estimates were reported separately by dose level. Stratum 2 patients were those with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
| Percent probability | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|
| Progression-free Survival for Stratum 2 (DIPG) Patients | 16.7 (0.0 to 37.9) | 26.7 (0.0 to 58.3) |
Complete or partial responses were considered responses. Response was evaluated by imaging or clinical progression. The response rate (percentage of participants with responses) is reported with a 95% Blyth-Still-Casella confidence interval. Response rates are reported separately by dose level.
| percentage | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|
| Overall Response Rate for Stratum 2 (DIPG) Patients | 0 (0.0 to 40.2) | 0 (0.0 to 63.2) |
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 are met for complete or partial response until the first date that recurrent or progressive disease was objectively documented.
No measurements were reported for this outcome.
Progression-free survival (PFS) was defined as the time interval from treatment initiation to date of first event (relapsed or progressive disease based on imaging or clinical progression or death from any cause) or to the date of last follow-up for patients without events. PFS was estimated using the method of Kaplan and Meier. The 1-year estimate of PFS is reported with a 95% confidence interval. PFS estimates were reported separately by dose level. Stratum 1 patients were those with recurrent or refractory primary malignant CNS tumors.
| Percent probability | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 |
|---|---|---|---|
| Progression-free Survival for Stratum 1 (Recurrent/Refractory) Patients | 0.00 (0 to 0) | 0 (0 to 0) | 10.7 (0.0 to 59.9) |
Serial blood samples for anti-drug-antibodies (ADA) were to be collected prior to dosing on courses 1, 2, 3, and 4, then every third course (courses 7 and 10), and then every 4 courses (courses 14, 18, 22, 26, 30, 34) until the end of therapy visit and collected into serum tubes. Percentages of patients with positive anti-drug antibodies with a 95% Blyth-Still-Casella confidence interval are reported by time point.
| percentage of patients with positive ADA | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Prior to Course 1 | 0 (0 to 77.64) | 0 (0 to 63.16) | 8.33 (0.43 to 34.89) | 0 (0 to 40.19) | 0 (0 to 52.71) |
| Prior to Course 2 | 33.33 (1.70 to 86.46) | 0 (0 to 63.16) | 0 (0 to 24.95) | 16.67 (0.85 to 59.81) | 0 (0 to 77.64) |
| Prior to Course 3 | 100 (50.0 to 100.0) | 0 (0 to 63.16) | 50.0 (9.76 to 90.24) | 50.0 (9.76 to 90.24) | 0 (0 to 77.64) |
| Prior to Course 4 | 100 (50.0 to 100.0) | 100 (50.0 to 100.0) | 50.0 (9.76 to 90.24) | 75 (24.86 to 98.73) | 0 (0 to 95.0) |
| Prior to Course 7 | — | 100 (50.0 to 100.0) | 50 (2.52 to 97.47) | 100 (50.0 to 100.0) | 0 (0 to 95.0) |
| Prior to Course 10 | — | — | 50 (2.52 to 97.47) | 100 (50.0 to 100.0) | — |
| Prior to Course 14 | — | — | 100 (50.0 to 100.0) | 100 (50.0 to 100.0) | — |
| Prior to Course 18 | — | — | 100 (50.0 to 100.0) | — | — |
| Prior to Course 22 | — | — | 0 (0 to 95.0) | — | — |
| Prior to Course 26 | — | — | 0 (0 to 95.0) | — | — |
| End of Treatment | 100 (22.36 to 100) | — | 33.33 (6.29 to 72.87) | 66.67 (13.54 to 98.30) | 0 (0 to 52.71) |
The cytokine was quantitated using V-PLEX Human Proinflammatory Panel, a multiplex immunoassay kit developed by Meso Scale Diagnostics (MSD). A four-parameter logistic fit calibration curve was generated and used to calculate concentrations in tested samples. Analyses were performed at pre-treatment and 1 week following the first dose of drug and additionally at 2, 3, 6, and 9 weeks following the course 1 drug dose if feasible. The mean concentration of TNF-alpha in pg/ml was reported with a standard deviation. When only one patient was analyzed, the standard deviation was reported as 0 (rather than undefined).
| pg/ml | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Week 0 | 0.95 ± 0 | 1.24 ± 0 | 0.71 ± 0.28 | 0.87 ± 0.48 | 0.41 ± 0.18 |
| Week 1 | 1.02 ± 0.22 | 1.31 ± 0.49 | 0.75 ± 0.19 | 0.92 ± 0.65 | 0.44 ± 0.10 |
| Week 2 | 0.92 ± 0.35 | 1.43 ± 0.01 | 0.97 ± 0.38 | 0.79 ± 0.33 | 1.03 ± 0 |
| Week 3 | 1.15 ± 0 | 1.42 ± 0.34 | 0.83 ± 0.35 | 1.12 ± 0.74 | 26.07 ± 35.73 |
| Week 6 | 1.07 ± 0 | 1.37 ± 0.54 | 0.79 ± 0.34 | 0.84 ± 0.40 | — |
| Week 9 | 1.57 ± 0 | 1.81 ± 0.83 | 0.83 ± 0.35 | 1.26 ± 0.60 | 0.35 ± 0 |
The cytokine was quantitated using V-PLEX Human Proinflammatory Panel, a multiplex immunoassay kit developed by Meso Scale Diagnostics (MSD). A four-parameter logistic fit calibration curve was generated and used to calculate concentrations in tested samples. Analyses were performed at pre-treatment and 1 week following the first dose of drug and additionally at 2, 3, 6, and 9 weeks following the course 1 drug dose if feasible. The mean concentration of IL-8 in pg/ml was reported with a standard deviation. When only 1 participant analyzed, the standard deviation was reported as 0 (rather than undefined).
| pg/ml | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Week 0 | 1.76 ± 0 | 5.88 ± 0 | 3.03 ± 0.80 | 4.91 ± 5.30 | 2.52 ± 1.18 |
| Week 1 | 1.29 ± 0.61 | 5.86 ± 4.17 | 4.67 ± 1.99 | 4.40 ± 2.34 | 1.52 ± 1.01 |
| Week 2 | 3.96 ± 0.60 | 4.27 ± 1.36 | 3.72 ± 1.30 | 2.74 ± 0.84 | 1.80 ± 0 |
| Week 3 | 3.82 ± 0 | 3.66 ± 1.91 | 3.73 ± 1.42 | 3.23 ± 0.99 | 217.42 ± 301.13 |
| Week 6 | 3.30 ± 0 | 3.94 ± 1.46 | 3.39 ± 2.06 | 2.54 ± 0.87 | — |
| Week 9 | 3.86 ± 0 | 10.71 ± 11.42 | 2.87 ± 0.70 | 3.03 ± 1.56 | 0.66 ± 0 |
Tumor mutation burden was defined as the number of somatic mutations per megabase. Average tumor mutation burden was reported with a standard deviation. When only one patient was analyzed, the standard deviation was reported as 0 rather than undefined.
| mutations per megabase | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Tumor Mutation Burden Based on Whole Exome Sequencing of Tumor Tissue | 2.62 ± 1.03 | 3.82 ± 2.79 | 3.95 ± 2.34 | 0.97 ± 0.0 | 4.83 ± 5.94 |
Tumor mutation burden was defined as the number of somatic mutations per megabase. Average tumor mutation burden was reported with a standard deviation. When only one patient was analyzed, the standard deviation was reported as 0 rather than undefined.
| mutations per megabase | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Tumor Mutation Burden Based on RNA Sequencing of Tumor Tissue | 3.15 ± 0.92 | 3.33 ± 0.32 | 3.26 ± 1.35 | — | — |
Mutation burden as detected by comparing the TCR sequencing of tumor tissue and/or PBMC. Mean numbers of clonotypes were reported by time point with standard deviations.
| Clonotyes | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Day 0 | — | — | — | 54688.25 ± 48633.55 | — |
| Day 7 | — | — | — | 159239.75 ± 47953.53 | — |
| Day 14 | — | — | — | 55328.25 ± 43692.86 | — |
| Day 21 | — | — | — | 127911.25 ± 135922.69 | — |
Collected over Approximately 3 years after start of treatment. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Stratum 1, Dose Level 1 | 0/3 (0%) | 0/3 (0%) | 3/3 (100%) |
| Stratum 1, Dose Level 2 | 1/3 (33.3%) | 0/3 (0%) | 3/3 (100%) |
| Stratum 1, Dose Level 3 | 5/14 (35.7%) | 4/14 (28.6%) | 14/14 (100%) |
| Stratum 2, Dose Level 2 | 4/6 (66.7%) | 1/6 (16.7%) | 6/6 (100%) |
| Stratum 2, Dose Level 3 | 4/5 (80%) | 5/5 (100%) | 5/5 (100%) |
| Event | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| Cytokine release syndromeImmune system disorders | 0/3 | 0/3 | 1/14 | 0/6 | 2/5 |
| Infusion related reactionInjury, poisoning and procedural complications | 0/3 | 0/3 | 3/14 | 0/6 | 0/5 |
| DysphagiaGastrointestinal disorders | 0/3 | 0/3 | 0/14 | 0/6 | 1/5 |
| FatigueGeneral disorders | 0/3 | 0/3 | 1/14 | 0/6 | 1/5 |
| Hepatic failureHepatobiliary disorders | 0/3 | 0/3 | 0/14 | 0/6 | 1/5 |
| Allergic reactionImmune system disorders | 0/3 | 0/3 | 0/14 | 0/6 | 1/5 |
| SepsisInfections and infestations | 0/3 | 0/3 | 0/14 | 0/6 | 1/5 |
| Upper respiratory infectionInfections and infestations | 0/3 | 0/3 | 0/14 | 0/6 | 1/5 |
| Aspartate aminotransferase increasedInvestigations | 0/3 | 0/3 | 1/14 | 0/6 | 1/5 |
| Neutrophil count decreasedInvestigations | 0/3 | 0/3 | 0/14 | 0/6 | 1/5 |
| Event | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 |
|---|---|---|---|---|---|
| White blood cell decreasedInvestigations | 1/3 | 3/3 | 9/14 | 3/6 | 3/5 |
| Alanine aminotransferase increasedInvestigations | 1/3 | 2/3 | 12/14 | 5/6 | 5/5 |
| Aspartate aminotransferase increasedInvestigations | 0/3 | 2/3 | 11/14 | 2/6 | 5/5 |
| Lymphocyte count decreasedInvestigations | 2/3 | 2/3 | 7/14 | 2/6 | 4/5 |
| AnorexiaMetabolism and nutrition disorders | 0/3 | 1/3 | 5/14 | 1/6 | 4/5 |
| Neutrophil count decreasedInvestigations | 1/3 | 2/3 | 5/14 | 2/6 | 2/5 |
| Platelet count decreasedInvestigations | 0/3 | 1/3 | 9/14 | 1/6 | 2/5 |
| HypertensionVascular disorders | 0/3 | 0/3 | 0/14 | 0/6 | 3/5 |
| Blood bilirubin increasedInvestigations | 0/3 | 0/3 | 3/14 | 0/6 | 3/5 |
| HypophosphatemiaMetabolism and nutrition disorders | 0/3 | 0/3 | 4/14 | 3/6 | 3/5 |
The one stratum 1, dose level 3 participant found to be ineligible after enrollment was excluded. Summary statistics for baseline characteristics are shown for eligible patients only (n=31).
| Age, Continuous(Year) | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 | Total |
|---|---|---|---|---|---|---|
| Median | 4.2 (3.4 to 14.6) | 13.2 (8.9 to 21.9) | 9.7 (2.2 to 20.6) | 6.6 (1.4 to 10.4) | 8.8 (2.8 to 10.6) | 8.9 (1.4 to 21.9) |
| Sex: Female, Male(Participants) | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 | Total |
|---|---|---|---|---|---|---|
| Female | 1 | 1 | 7 | 4 | 5 | 18 |
| Male | 2 | 2 | 7 | 2 | 0 | 13 |
| Ethnicity (NIH/OMB)(Participants) | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 | Total |
|---|---|---|---|---|---|---|
| Hispanic or Latino | 1 | 1 | 4 | 3 | 2 | 11 |
| Not Hispanic or Latino | 2 | 1 | 9 | 3 | 2 | 17 |
| Unknown or Not Reported | 0 | 1 | 1 | 0 | 1 | 3 |
| Race (NIH/OMB)(Participants) | Stratum 1, Dose Level 1 | Stratum 1, Dose Level 2 | Stratum 1, Dose Level 3 | Stratum 2, Dose Level 2 | Stratum 2, Dose Level 3 | Total |
|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 0 | 0 | 1 | 2 |
| Asian | 0 | 0 | 1 | 0 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 1 | 0 | 1 | 2 |
| White | 2 | 3 | 10 | 4 | 0 | 19 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 2 | 2 | 3 | 7 |
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Pediatric Brain Tumor Consortium