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Figure, Table, and MRI acquisition protocol

Purpose:Targeting tumor blood vessels is an attractive therapy in glioblastoma (GBM), but the mechanism of action of these agents and how they modulate delivery of concomitant chemotherapy are not clear in humans. We sought to elucidate how bevacizumab modulates tumor vasculature and the impact those vascular changes have on drug delivery in patients with recurrent GBM.Experimental Design:Temozolomide was labeled with [11C], and serial PET-MRI scans were performed in patients with recurrent GBM treated with bevacizumab and daily temozolomide. PET-MRI scans were performed prior to the first bevacizumab dose, 1 day after the first dose, and prior to the third dose of bevacizumab. We calculated tumor volume, vascular permeability (Ktrans), perfusion (cerebral blood flow), and the standardized uptake values (SUV) of [11C] temozolomide within the tumor.Results:Twelve patients were enrolled, resulting in 23 evaluable scans. Within the entire contrast-enhancing tumor volume, both temozolomide uptake and vascular permeability decreased after initiation of bevacizumab in most patients, whereas change in perfusion was more variable. In subregions of the tumor where permeability was low and the blood–brain barrier not compromised, increased perfusion correlated with increased temozolomide uptake.Conclusions:Bevacizumab led to a decrease in permeability and concomitant delivery of temozolomide. However, in subregions of the tumor where permeability was low, increased perfusion improved delivery of temozolomide, suggesting that perfusion may modulate the delivery of chemotherapy in certain settings. These results support exploring whether lower doses of bevacizumab improve perfusion and concomitant drug delivery.

Glioblastoma is immunologically “cold”, with little clinical response to single-agent immune-checkpoint inhibitors (ICI). Our previous randomized study of neoadjuvant and adjuvant pembrolizumab versus adjuvant pembrolizumab in recurrent glioblastoma identified a molecular signature for ICI and suggested that neoadjuvant pembrolizumab improved survival (PMID30742122). We extended these original findings with a single-arm expansion cohort of glioblastoma patients at first or second relapse undergoing surgical resection for recurrent disease. Eligibility was identical to the original study. Patients receiving > 4mg dexamethasone, or with prior immunotherapy or anti-angiogenic therapy were excluded. The primary objective was to determine the effect of neoadjuvant pembrolizumab on cell cycle/cancer proliferation genes. Secondary objectives were PFS-6 and OS. Twenty-five patients received neoadjuvant pembrolizumab followed by tumor resection and adjuvant pembrolizumab until progression or unacceptable toxicity. The median age of participants was 60 years and median KPS was 90. Ninety-six percent of tumors were IDH wild-type and 48% were MGMT promoter methylated. Neoadjuvant pembrolizumab continued to induce alterations in the tumor microenvironment (T-cell/IFN upregulation, cell cycle downregulation; molecular responders (MR)), but the proportion of MR in this trial was 36% compared with 70% in the original treatment cohort. Median OS was 6.8 months. There were no CTCAE grade 4-5 AEs attributable to pembrolizumab. Further analysis of prognostic differences between stage 1 and 2 subjects is underway, as are additional immune and genotypic correlates to further define molecular changes induced by pembrolizumab. Anti-PD1 monotherapy triggers an intra-tumoral genetic signature associated with interferon-γ response and suppression of cell cycle/cancer proliferation in recurrent glioblastoma, though does not extend OS. This surgical window-of-opportunity paradigm allows for attribution of molecular effects to single agents. Future work will evaluate the differences in patient population, tumor characteristics, and address additional immune checkpoints and/or signaling pathways that can be targeted to augment the effectiveness of anti-PD1 in glioblastoma.

Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson’s r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPK-pathway alterations, and patients with relatively high CBF.

BACKGROUND: Absolute quantification of metabolites in MR spectroscopic imaging (MRSI) requires a stable reference signal of known concentration. The Electronic REference To access In vivo Concentrations (ERETIC) has shown great promise but has not been applied in patients and 3D MRSI. ERETIC hardware has not been integrated with receive arrays due to technical challenges, such as coil combination and unwanted coupling between multiple ERETIC and receive channels, for which we developed mitigation strategies. PURPOSE: To develop absolute quantification for whole-brain MRSI in glioma patients. STUDY TYPE: Prospective. POPULATION: Five healthy volunteers and three patients with isocitrate dehydrogenase mutant glioma (27% female). Calibration and coil loading phantoms. FIELD STRENGTH/SEQUENCE: A 3T; Adiabatic spin-echo spiral 3D MRSI with real-time motion correction, Fluid Attenuated Inversion Recovery (FLAIR), Gradient Recalled Echo (GRE), Multi-echo Magnetization Prepared Rapid Acquisition of Gradient Echo (MEMPRAGE). ASSESSMENT: Absolute quantification was performed for five brain metabolites (total N-acetyl-aspartate [NAA]/creatine/choline, glutamine + glutamate, myoinositol) and the oncometabolite 2-hydroxyglutarate using a custom-built 4x-ERETIC/8x-receive array coil. Metabolite quantification was performed with both EREIC and internal water reference methods. ERETIC signal was transmitted via optical link and used to correct coil loading. Inductive and radiative coupling between ERETIC and receive channels were measured. STATISTICAL TESTS: ERETIC and internal water methods for metabolite quantification were compared using Bland–Altman (BA) analysis and the nonparametric Mann–Whitney test. P < 0.05 was considered statistically significant. RESULTS: ERETIC could be integrated in receive arrays and inductive coupling dominated (5–886 times) radiative coupling. Phantoms show proportional scaling of the ERETIC signal with coil loading. The BA analysis demonstrated very good agreement (3.3% ± 1.6%) in healthy volunteers, while there was a large difference (36.1% ± 3.8%) in glioma tumors between metabolite concentrations by ERETIC and internal water quantification. CONCLUSION: Our results indicate that ERETIC integrated with receive arrays and whole-brain MRSI is feasible for brain metabolites quantification. Further validation is required to probe that ERETIC provides more accurate metabolite concentration in glioma patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1

The molecular genetic understanding of nervous system tumors has expanded rapidly offering insight into potentially targetable oncogenic driver alterations. In monogenic tumor susceptibility syndromes such as tuberous sclerosis, neurofibromatosis type 1, and von Hippel Lindau syndrome targeted drugs have demonstrated efficacy and are now approved in the United States for the treatment of subependymal giant cell astrocytoma, plexiform neurofibroma, and hemangioblastoma, respectively. Some genetic alterations like BRAF V600E mutations or neurotrophic receptor tyrosine kinase (NTRK) fusions, occur across multiple cancers, including certain types of gliomas. Dabrafenib in combination with trametinib is approved for use in gliomas that harbor BRAF V600E mutations and larotrectinib is approved in gliomas that harbor certain NTRK fusions. In pediatric low-grade astrocytoma, one of the most common solid tumors of childhood, BRAF truncation-fusion events may render these tumors susceptible to tovorafenib, a type 2 RAF inhibitor, which is under study in clinical trials. Mutations in the isocitrate dehydrogenase (IDH) gene occur in the majority of low-grade and anaplastic gliomas, create specific metabolic vulnerabilities, and several IDH-mutant targeting strategies are under investigation. Glioblastoma is characterized by intratumoral molecular heterogeneity so strategies that target single genetic alterations may not be as effective as in other types of gliomas although a number of novel targeted strategies have been advanced to clinical trials. Other types of nervous system tumors such as medulloblastoma, meningioma, primary central nervous system diffuse large B-cell lymphoma, and craniopharyngioma harbor targetable genetic alterations and clinical trials are ongoing. Finally, metastatic brain tumors may harbor targetable genetic alterations that may differ from the primary site of cancer highlighting the importance of biopsy and molecular analysis of the brain metastases in order to enroll patients in clinical trials of targeted therapies.

PURPOSE Hypoxia from inhibition of angiogenesis reduces DNA repair capacity. Targeting homologous recombination pathway also has anti-angiogenic effects. To examine the synergistic effects of disrupting DNA repair pathways and angiogenesis in glioblastoma, we combine cediranib (ced), a pan vascular endothelial growth factor (VEGF) receptor inhibitor with olaparib (ola), a poly-ADP ribose polymerase (PARP) inhibitor compared with bevacizumab (bev), a VEGF-A inhibitor alone. To identify potential biomarkers predicting response to treatments, we also perform whole exome sequencing on archival tissues. METHODS Bevacizumab-naïve adult patients with first or second recurrence of glioblastoma after radiation and temozolomide were randomly assigned to cediranib (30mg PO daily)/olaparib (200mg PO twice daily) or bevacizumab (10mg/kg IV every 2 weeks). The primary end point was progression-free survival (PFS) at 6 months. The secondary end points included safety and overall survival (OS). Whole exome sequencing of formalin-fixed paraffin embedded archival tissue from 23 patients was performed. RESULTS We are presenting the final data from this trial. Between December 2017 and November 2018, a total 70 adult patients with recurrent glioblastoma were randomly assigned to receive ced/ola (n = 35) or bev (n = 35). With a data cut off on 5/30/2022, median PFS was 118 days and 92 days in ced/ola and bev groups, respectively (hazard ratio, 1.099, 95% CI 0.6-2, p = 0.76). Median overall survival was 269.5 days and 192 days in ced/ola and bev groups, respectively (hazard ratio, 0.6892, 95% CI 0.39-1.2, p = 0.2). Whole exome sequencing was performed in total 23 patients (24 samples), 14 patients in the ced/ola group and 9 patients in the bev group. CONCLUSION No significant survival benefit was observed in patients with recurrent glioblastoma treated with ced/ola compared to patients treated with bev monotherapy. Potential biomarkers predicting response to treatment identified from the whole exome sequencing on archival tissues will be presented.

Purpose Although maximal resection of wild-type GBM tumors is associated with longer survival, the association of genomic alterations with the ability to resect disease has not been elucidated. This study aimed to determine whether certain molecular alterations are less amenable to surgical resection and whether achieving a surgical margin devoid of tumor cell burden provides a clinical benefit. Methods Molecular profiling of 148 consecutive tumor samples from newly diagnosed patients with IDH-WT GBM SNaPshot genotyping, and methylation-specific PCR for MGMT promoter methylation. The association of alterations with residual volume and progression-free survival was evaluated in regression analyses. We prospectively investigated the impact of TERTp status at the surgical margin on progression-free survival (PFS) in 47 patients. PFS and overall survival (OS) were evaluated with the log-rank test and Cox regression models.Results Overall, 148 patients (91 men [61.5%], median age, 62.5 years [range 56–70 years] had maximally safe surgery. The median follow-up duration was 18 months (IQR, 4-32 months). The rate of PFS was significantly lower in MGMT promoter unmethylated IDH-WT GBM amenable to resection with residual volume >4.9cc (hazard ratio [HR], 2.35; 95% CI, 1.44-3.84; P=.005). Gene amplification (PDGFRA, KIT, KDR) on 4q12 and TP53 and RB1 mutations were associated with greater RV. Prospective trial revealed median PFS for tumors with TERTp mutations in the surgical margin was 10.1 months while tumors with undetectable TERTp mutations in the margin did not progress (median follow-up 8.1 months, IQR 1.6-14.6). Surgical tumor margins devoid of TERTp mutations were associated with significantly different probability of PFS (0.23; 95%CI 0.15-0.43; P< 0.01)Conclusion In conclusion, 4q12 amplification (KDR/PDGFRA/KIT) and tumor suppressor gene alterations (RB1, TP53) were associated with greater residual volume. Tumor-free margins defined spatially by intraoperative navigation as assessed by quantifying TERTp mutation allelic fraction was correlated with prolonged PFS.

BACKGROUND Adverse events (AE) including seizures cause significant morbidity in patients with GBM. We propose a novel method for assessing genomic predictors of AEs using results from a clinical targeted sequencing platform with variant function analysis. METHODS We identified 1,011 consecutive adult patients with newly diagnosed, histologically confirmed IDH-wildtype GBM with targeted exome NGS (Oncopanel) at Dana-Farber Cancer Institute from 2013-2019. Seizure at presentation was retrospectively identified as an AE. Biologic function (high loss, low loss, neutral, low gain and high gain) was assigned to variants using a three-tiered approach leveraging a genetic variant database (OncoKB), followed by analysis using protein prediction tools (Sift, Polyphen2 and Provean). Univariate logistic regression was performed for each relevant altered gene against the outcome of interest with false-discovery rate correction. Genes associated with seizure at presentation were included iteratively in a multivariate logistic model including other predictors of the outcome. RESULTS Our analysis included 470 GBM patients with 107 genes and 12 whole chromosome or arm level candidate variants covered by all versions of Oncopanel and with >10% alteration. Seizure at presentation occurred in 143/463 patients (31%) and was associated with EGFR amplification (high gain) (OR: 2.76, 95% CI: 1.4-5.3, p = 0.04). In a multivariate analysis (including age, sex, and preoperative tumor volume), EGFR amplification remained statistically significant (OR: 1.5, 95% CI: 1.0-2.2, p = 0.03). CONCLUSION Genomic biomarkers based on functional variant analysis of a routine clinical panel may predict adverse events in GBM. Seizure at presentation was independently associated with EGFR amplification. Our ongoing analysis will look at predictors of myelosuppression, thromboembolism, pseudoprogression and early progression using a similar approach. Identifying molecular risk factors could improve the management of patients through supportive care and consideration of prophylactic therapies.

BACKGROUND CAN-3110 (rQNestin34.5v2) is an HSV-1 oncolytic viral immunotherapy with one copy of the inflammatory ICP34.5 gene under transcriptional control of the Nestin glioma-specific promoter. We completed a phase 1 sequential dose-escalation trial of CAN-3110 in recurrent high-grade glioma (rHGG). METHODS CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose- escalated by half log up to 1x1010 pfu in biopsy confirmed rHGG. An expansion cohort of 12 patients was then accrued at 1x109 pfus. Blood and post-injection rHGG were collected. RESULTS 41 rHGG patients were treated (42 separate interventions): median age 56 years (range 27-74); 21 females, 20 males; median baseline KPS 90 (range 70-100). CAN-3110 administration was well-tolerated with no dose limiting toxicities. Median overall survival (mOS) was 11.9 months. Histologic and molecular analyses showed significantly increased T cell infiltration in post treatment samples with elevated T cell and/or B cell receptor (TCR/BCR) transcripts which correlated with patient survival (HR 0.26 for patients with elevated TCR/BCR rearrangements as compared to patients with low). Volumetric analyses of MRI suggest a trend between reduction in the relative change in tumor growth, TCR/BCRs enrichment and survival in CAN-3110 treated patients. CLINICAL IMPLICATIONS Administration of CAN-3110 into rHGG was well tolerated. OS of CAN-3110 treated subjects compare favorably to historical controls. The association of increased TCR/BCR transcripts with survival suggests that CAN-3110 induces T cell responses against rHGG, supporting further clinical development of CAN-3110 viral immunotherapy.

The optimal treatment for newly diagnosed and refractory or relapsed primary central nervous system lymphoma (PCNSL) is not fully defined. We review the epidemiology, clinical presentation, and current management strategies for newly diagnosed PCNSL as well as emerging treatments for refractory and relapsed disease.In recent decades, the incidence of PCNSL has increased in the elderly population. With advancements in chemotherapy for PCNSL, survival has improved. However, outcomes remain inferior when compared with other forms of extranodal lymphoma. Additionally, treatments can be associated with clinically significant neurotoxicities. Despite advances in the treatment of PCNSL, current treatment regimens remain suboptimal in terms of response rates and neurotoxicity. Well-tolerated agents, especially for the elderly, are still needed.

2030 Background: Glioblastoma (GBM) and tumor endothelial cells express phosphatidylserine (PS), a highly immunosuppressive membrane phospholipid. PS receptors engage with immune cells, leading to expansion of myeloid-derived suppressor cells (MDSCs) which promote an immunosuppressive and pro-angiogenic tumor microenvironment. Bavituximab (BAV) – a chimeric monoclonal antibody – binds to β2-glycoprotein 1 (β2-GP1) to form a complex of β2-GP1 with PS, resulting in immune activation against tumor cells and anti-angiogenic effects. Pre-clinical data in GBM models suggest synergistic effects of PS blockade, radiation (RT), and temozolomide (TMZ). Here, we present results from a phase II trial (NCT03139916) of BAV, RT and TMZ in GBM patients. Methods: 33 adults with newly diagnosed IDH-wild-type GBM were enrolled and received 6 weeks of RT+TMZ, followed by 6 cycles of TMZ. BAV (3 mg/kg) was given weekly, starting at week 1 of RT+TMZ, for 18 weeks with the option to continue if tolerated. The primary endpoint was the proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥ 72%. As an exploratory endpoint, the immune profile in tumor tissue and peripheral blood mononuclear cells (PBMCs) was assessed using nanoString and multispectral immunofluorescence, with the goal to assess on-target effects of BAV in longer vs. shorter surviving patients (split based on median survival). Relative cerebral blood flow (rCBF) from dynamic susceptibility contrast MRI was also obtained. Results: 24 patients were alive at 12 months and OS-12 was 73% (95% CI 59-90%) so the study met its primary endpoint. Median OS was 15.4 months. As best response, 79% of patients had stable disease, 12% had a partial response and 9% had progressive disease. Eight grade 3 or 4 adverse events were seen (no grade 5 AEs). Ten pre-treatment and 7 post-treatment tissue samples were available. Analysis of RNA from pre-treatment tumor specimens showed a significantly positive shift in myeloid-related gene expression in patients with longer survival, with enrichment of 116 and 120 transcripts as well as downregulation of 2 and 1 gene for PFS and OS, respectively. There was no differential expression in PBMCs. Including all tissue samples, there was a marked reduction of MDSCs after BAV compared to time of diagnosis (p = 0.011). Decreased rCBF post-RT/pre-cycle 1 TMZ was associated with improved OS (HR 4.63, p = 0.029). Conclusions: OS-12 was 73%, meeting the primary endpoint and suggesting potential activity of BAV in newly diagnosed GBM. BAV leads to on-target depletion of intratumoral immunosuppressive MDSCs and anti-angiogenic effects. As expected, based on the mechanism of action of BAV, there was no difference in PBMC gene expression profile in patients with long and short survival. Combining BAV with immune checkpoint inhibitors in the future may augment tumor immune response. Clinical trial information: NCT03139916.

Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation have no proven therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has induced early responses in patients with H3 K27M-mutant DMG. We performed an integrated pre-clinical and clinical assessment of ONC201 treatment, in order to define response rates in H3 K27M-mutant DMG patients and to clarify predictors of response. ONC201 was effective in murine H3 K27M-mutant gliomas with excellent CNS penetration and survival benefit. H3 K27M-mutant DMG patients treated with ONC201 on active clinical trials (n=50) showed significant survival benefit in recurrent and non-recurrent settings, with multiple sustained responses. Tumor sequencing from treated patients demonstrates an EGFR/FOXG1-driven telencephalic gene regulatory network that imparts a critical resistance phenotype to ONC201. Genetic and pharmacologic knockdown of EGFR in H3 K27M-mutant cell cultures results in improved sensitivity to ONC201 and reduced FOXG1 enhancer binding, suggesting possible future combinatorial opportunities.

BACKGROUND EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated. RESULTS There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

There is a wide variety of intra-axial primary and secondary brain neoplasms. Many of them have characteristic imaging features while other tumors can present in a similar fashion. There are peculiar posttreatment imaging phenomena that can present as intra-axial mass-like lesions (such as pseudoprogression or radiation necrosis), further complicating the diagnosis and clinical follow-up of patients with intracerebral tumors. The purpose of this chapter is to present a general overview of the most common intra-axial brain tumors and peculiar posttreatment changes that are very important in the diagnosis and clinical follow-up of patients with brain tumors.

This chapter will review the challenges in pharmacotherapy in primary brain tumors that include the presence of the blood-brain barrier, a blood-tumor barrier, active drug efflux pumps, and high plasma protein binding of agents. The approaches to improve the delivery of drugs to the brain will be discussed. Often the management of brain tumors involves the use of corticosteroids and enzyme-inducing antiseizure medications that can have significant drug interactions that may impact the efficacy or toxicity of drugs used to treat these patients. Various techniques used to assess drug distribution to the brain will be reviewed.

A preliminary evaluation of the efficacy of irinotecan in patients with malignant glioma demonstrated modest activity. A markedly lower than expected incidence of drug-related toxicity was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of irinotecan in this patient population was considerably greater than in colorectal cancer patients. Concomitant medications used chronically in brain cancer patients, especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in patients with recurrent malignant gliomas to independently determine the maximum tolerated dose (MTD) of irinotecan in patients stratified according to the use of enzyme-inducing anticonvulsants (EIAs).Patients with recurrent malignant gliomas received irinotecan as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m(2)/week for both groups of patients (+/-EIA). Groups of/==" BORDER="0"3 patients were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of irinotecan, its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and the glucuronide conjugate of SN-38, SN-38 glucuronide, were determined in all patients during treatment with the first weekly dose.Forty patients were enrolled into the study and treated with a total of 135 cycles of irinotecan. The MTD was determined to be 411 mg/m(2)/week in the +EIA cohort and 117 mg/m(2)/week in the -EIA cohort for the weekly x 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan was distinctly dose dependent in the patients receiving EIAs, decreasing from approximately 50 liters/h/m(2) at the lower dose levels (125-238 mg/m(2)) to a mean +/- SD value of 29.7 +/- 9.0 liters/h/m(2) (n = 7) at the MTD. The grand mean CL for a group of 13 patients who were not taking EIAs, 18.8 +/- 10.6 liters/h/m(2), was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of SN-38 (P = 0.4) and SN-38 glucuronide (P = 0.55) were not significantly different at the MTDs for the two cohorts of patients.The MTD of irinotecan was 3.5 times greater in patients with malignant glioma who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of irinotecan. These findings have important implications for subsequent clinical trials to further evaluate irinotecan in brain cancer patients and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.

Drugs currently available for intrathecal administration are cleared rapidly from the CSF. DepoCyt is a slow-release formulation of cytarabine that maintains cytotoxic concentrations of free cytarabine in the CSF for14 days following a single injection. DepoCyt was administered to 110 patients with a diagnosis of neoplastic meningitis based on either a positive CSF cytology (76) or neurologic and CT or MRI scan findings sufficient to document neoplastic meningitis (34). Patients were treated with DepoCyt 50mg every 2 weeks for 1 month of induction therapy by either lumbar puncture (LP) or intraventricular (IVT) injection. Patients without neurologic progression were candidates to receive an additional 3 months of consolidation therapy. All patients received dexamethasone 4 mg BID on days 1-5 of each cycle. Median time to neurologic progression was 55 days; median overall survival was 95 days. Among the 76 patients with a positive CSF cytology at baseline, 70 were evaluable for response, and of this group 19 (27%) attained the criteria for response (cytologic response in the absence of neurologic progression). The most important adverse events were headache and arachnoiditis. When drug-related, these were largely low grade, transient, and reversible. Drug-related grade 3 headache occurred on 4% of cycles; grade 3 or 4 arachnoiditis occurred on 6% of cycles. No cumulative toxicity was observed. DepoCyt injected once every 2 weeks produced a response-rate comparable to that previously reported for methotrexate given twice a week. The once in every 2-week-dosing interval offers an advantage over conventional schedules (2-3 doses/week) used for other agents available for intrathecal injection.

Abstract 959 Background: We recently studied the safety and activity of intraventricular rituximab monotherapy in the treatment of recurrent intraocular and CNS non-Hodgkin lymphoma (NHL) (JCO 2007 25: 1350–1356). Rapid dissemination throughout the craniospinal axis was demonstrated and cytologic responses were detected in six out of ten patients. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. The major goals of this current trial are to perform the first study of intraventricular immuno-chemotherapy in humans and to evaluate the safety of two dose levels of intraventricular rituximab as well as its pharmacokinetics in combination with intraventricular methotrexate (MTX). Secondary goals are to obtain information regarding the efficacy of this approach in the treatment of patients with recurrent CNS lymphoma, (brain parenchyma, intraocular or the leptomeningeal compartment). Methods: Thirteen patients with recurrent/refractory CD20+ CNS NHL were treated at UCSF, Dana Farber Cancer Institute and Massachusetts General Hospital on a phase I clinical trial involving twice weekly intraventricular rituximab at 10 mg and 25 mg dose levels, administered over a planned four week schedule. Rituximab is combined with MTX (12 mg) during the second intraventricular injection each week. Patients achieving partial response or better were eligible for a second month of combination intraventricular rituximab plus MTX. Results: No serious treatment-related toxicity has been detected with intraventricular rituximab/MTX at the 10 mg and 25 mg dose levels. The most common treatment-related toxicity was paresthesias (grade 1). One patient exhibited NHL progression outside of the CNS at three weeks and thus was not evaluable for CNS response, and one patient exhibited stable disease. Complete cytologic responses were detected in ten out of thirteen patients at the one-month restaging. Parenchymal responses were detected in three out of six subjects with one partial response within the corpus callosum, and two complete regressions of lesions within temporal lobe and cerebral cortex. One patient with leptomeningeal lymphoma non-responsive to intravenous rituximab and refractory to high-dose intravenous and intrathecal methotrexate, oral temozolomide and intrathecal liposomal cytarabine, obtained a sustained complete response with the intraventricular rituximab/MTX protocol and subsequently was approved for consolidative autologous stem cell transplant. Two patients have participated in extended dosing on protocol without progression for five and eight months respectively. Thus far, there is no evidence for a relationship between FcGR3A polymorphism and therapeutic resistance in a preliminary analysis (n=8 patients). The maximum tolerated dose of intraventricular rituximab with this combination was established as 25 mg. The mean maximum intraventricular rituximab concentration after intraventricular injection of rituximab was 285 microgram/ml at the 10 mg dose level (N=3) and 882 microgram/ml at the 25 mg dose level (N=10); (p Conclusions: Intraventricular rituximab/MTX appears to be safe in recurrent CNS NHL. Twelve of thirteen patients completed at least one month of therapy, without any treatment-associated serious adverse events at any of the institutions. Intraventricular administration of methotrexate may significantly attenuate rituximab clearance from the leptomeningeal compartment. There is encouraging evidence for significant activity of intraventricular immuno-chemotherapy in the treatment of drug-resistant CNS NHL, refractory or non-responsive to intravenous rituximab. These results provide strong support for further investigation of this novel therapeutic approach. NCT00221325. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures: Off Label Use: We will discuss the off-label use of rituximab within the leptomeningeal compartment to treat recurrent/refractory CNS lymphomas. Advani:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Farming is Farming. 44 minutes. 1976. RAM films. Merchants of Grain. 57 minutes. 1983. Filmmakers Library. One More Year on the Family Farm? 22 minutes. 1977. CORT. Potatoes. 28 minutes. 1977. Bullfrog Films. The Small Farm in America. 28 minutes. 1978. RAM films. Waterloo Farmers. 28 minutes. 1979. Bullfrog Films.