Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB).
Adult patients ...enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available.
A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses.
Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.
Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and ...associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (
n
= 43), whole-exome sequencing (
n
= 26), and RNA-sequencing (
n
= 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (
P
= 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (
P
= 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B–like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes
DICER1
,
DROSHA
, and
DGCR8
were recurrent and mutually exclusive in PB-B and PB-B–like subgroups; PB-FOXR2 samples universally overexpressed the
FOXR2
proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.
The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular ...endothelial growth factor, in combination with irinotecan.
This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging.
The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli).
Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.
Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are ...currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age:
p
= 0.011, gender:
p
= 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.
Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available
salvage therapy. This study was conducted to determine if the ...combination of a novel antiangiogenic therapy, bevacizumab,
and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma.
Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence
of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab
and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was
determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m 2 , whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m 2 . Toxicity and response were assessed.
Results: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted
in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival
was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade
III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was
72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli,
and one patient had an arterial ischemic stroke.
Conclusions: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.
To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with ...refractory or recurrent CNS malignancies.
MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752.
Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1).
MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily.
Purpose
We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality ...therapy.
Methods
We reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed.
Results
Median age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively.
Conclusions
Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG).
Eligible patients received two ...doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast-enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ.
Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure.
BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.
Background
We evaluated circulating levels of immunosuppressive regulatory T cells (T
regs
) and other lymphocyte subsets in patients with newly diagnosed medulloblastoma (MBL) undergoing surgery ...compared to a control cohort of patients undergo craniectomy for correction of Chiari malformation (CM) and further determined the impact of standard irradiation and chemotherapy on this cell population.
Methods
Eligibility criteria for this biologic study included age 4–21 years, patients with CM undergoing craniectomy (as non-malignant surgical controls) and receiving dexamethasone for prevention of post-operative nausea, and those with newly diagnosed posterior fossa tumors (PFT) undergoing surgical resection and receiving dexamethasone as an anti-edema measure. Patients with confirmed MBL were also followed for longitudinal blood collection and analysis during radiotherapy and chemotherapy.
Results
A total of 54 subjects were enrolled on the study 22-CM, 18-MBL, and 14-PFT. Absolute number and percentage T
regs
(defined as CD4
+
CD25
+
FoxP3
+
CD127
low/−
) at baseline were decreased in MBL and PFT compared to CM
p
= 0.0016 and 0.001, respectively). Patients with MBL and PFT had significantly reduced overall CD4
+
T cell count (
p
= 0.0014 and 0.0054, respectively) compared to those with CM. Radiation and chemotherapy treatment in patients with MBL reduced overall lymphocyte counts; however, within the CD4
+
T cell compartment, T
regs
increased during treatment but gradually declined post therapy.
Conclusions
Our results demonstrate that patients with MBL and PFT exhibit overall reduced CD4
+
T cell counts at diagnosis but not an elevated proportion of T
regs
. Standard treatment exacerbates lymphopenia in those with MBL while enriching for immunosuppressive T
regs
over time.
Purpose: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade
4 malignant glioma, salvage therapies following recurrence offer ...essentially palliative benefit. We did a phase II trial of
bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with
recurrent grade 3 malignant glioma.
Experimental Design: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan
every 14 days, a second cohort ( n = 24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle.
For both cohorts, the dose of irinotecan was 340 mg/m 2 for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m 2 for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance
imaging.
Results: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95%
confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two
treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient,
and one patient who developed thrombotic thrombocytopenic purpura.
Conclusion: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant
glioma.
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