ABSTRACT
Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
Subject(s)
Glioblastoma , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Glioblastoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Antibodies, Monoclonal, Humanized , Oncolytic Virotherapy/adverse effects , Oncolytic Viruses/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD). METHODS: This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer. RESULTS: Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2-19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2-20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. CONCLUSION: This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.
Subject(s)
Breast Neoplasms , Meningeal Carcinomatosis , Humans , Female , Trastuzumab/adverse effects , Receptor, ErbB-2/metabolism , Breast Neoplasms/pathology , Meningeal Carcinomatosis/drug therapy , Meningeal Carcinomatosis/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in â¼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas. PATIENTS AND METHODS: Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy. RESULTS: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors. CONCLUSIONS: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.
Subject(s)
Glioma , Neoplasm Recurrence, Local , Adult , Follow-Up Studies , Glioma/drug therapy , Glioma/genetics , Humans , Microtubule-Associated Proteins , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Phenylurea Compounds , Protein Kinase Inhibitors/adverse effects , Pyrimidines , Receptor, Fibroblast Growth Factor, Type 3/geneticsABSTRACT
BACKGROUND: For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-ßRII receptor (a TGF-ß "trap") fused to a human IgG1 antibody blocking PD-L1. METHODS: In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety. RESULTS: As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with IDH-mutant GBM (n = 6) and 13.8% (3.9-31.7%) for patients with IDH-wild-type GBM (n = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n = 6]). CONCLUSIONS: The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.
ABSTRACT
PURPOSE: The CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration. METHODS: CSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response. RESULTS: Fifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0-200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2-3 months prior to changes seen on MRI, and while CSF cytology remained negative. CONCLUSION: Our study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.
Subject(s)
Biomarkers, Tumor/cerebrospinal fluid , Breast Neoplasms/pathology , Meningeal Carcinomatosis/secondary , Neoplastic Cells, Circulating/pathology , Receptor, ErbB-2/metabolism , Trastuzumab/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Breast Neoplasms/cerebrospinal fluid , Breast Neoplasms/drug therapy , Female , Follow-Up Studies , Humans , Injections, Spinal , Meningeal Carcinomatosis/cerebrospinal fluid , Meningeal Carcinomatosis/drug therapy , Neoplastic Cells, Circulating/metabolism , Prognosis , Survival RateABSTRACT
BACKGROUND: Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab. METHODS: This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPSâ ≥60, and no prior bevacizumab or HDAC inhibitors. RESULTS: Ninety patients (bevacizumabâ +â vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumabâ +â vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, Pâ =â 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, Pâ =â 0.08]), median OS (7.8 vs 9.3 mo, Pâ =â 0.64, HR 0.93 [95% CI: 0.5, 1.6, Pâ =â 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n =â 37), neurological changes (n =â 2), anorexia (n =â 2), infections (n =â 9), wound dehiscence (n =â 2), deep vein thrombosis/pulmonary embolism (n =â 2), and colonic perforation (n =â 1). CONCLUSIONS: Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.
Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bayes Theorem , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Humans , Neoplasm Recurrence, Local/drug therapy , VorinostatABSTRACT
RATIONALE: 2-Hydroxyglutarate (2-hg) exists as enantiomers and can readily undergo cyclization to its lactone. Gas chromatography/electron ionization mass spectrometry (GC/EI-MS) has been used to separate 2-hg enantiomers in bodily fluids but the assay cannot simultaneously measure cyclic and acylic 2-hg enantiomers. Furthermore, the assignment of ion structures was not verified by complementary MS data. METHODS: GC/EI-MS and product ion analysis were used to obtain MS and MS/MS spectra of 2-hg, deuterated and 13 C-labeled 2-hg, and 2-hg lactone. Ion structures and EI fragmentation mechanisms were determined by fragmentation pattern and isotopologue comparisons. Using the EI data, a GC/MS/MS assay was developed to separate and detect 2-hg enantiomers and 2-hg lactone enantiomers in blood and urine using a cyclodextrin capillary column. RESULTS: A new ion structure was predicted for the 85 m/z fragment than what was previously hypothesized, and the 117 m/z ion was the only fragment unique to the linear 2-hg compound. MS/MS data suggested that the majority of the fragments were the result of secondary fragmentation. Finally, separation of serum and urine 2-hg and 2-hg lactone enantiomers was achieved, and the acyclic 2-hg compound was found to be the major compound detected, though the amount of lactone detected was considerable in a number of samples. CONCLUSIONS: Unique EI fragmentation pathways for both 2-hg and the 2-hg lactone have been described. Subsequently, the GC/MS/MS assay presented herein has significant potential as a novel clinical assay as it separates and detects both 2-hg enantiomers and the 2-hg lactone enantiomers, a capability which has not been previously demonstrated by any other assay to date.
Subject(s)
Gas Chromatography-Mass Spectrometry/methods , Glutarates/chemistry , Lactones/chemistry , Molecular Structure , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Tandem Mass Spectrometry/methodsABSTRACT
Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a surrogate for tumor tissue in the management of both primary and secondary brain tumors. Herein we critically review available literature on spinal fluid and plasma circulating tumor cells (CTCs) and cell-free tumor (ctDNA) for diagnosis and monitoring of leptomeningeal and parenchymal brain metastases. We discuss technical issues and propose several potential applications of liquid biopsies in different clinical settings (ie, for initial diagnosis, for assessment during treatment, and for guidance of treatment decisions). Last, ongoing clinical studies on CNS metastases that include liquid biopsies are summarized, and recommendations for future clinical studies are provided.
Subject(s)
Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/genetics , Circulating Tumor DNA/analysis , Liquid Biopsy/methods , Neoplastic Cells, Circulating/pathology , Central Nervous System Neoplasms/blood , Central Nervous System Neoplasms/therapy , Circulating Tumor DNA/genetics , Clinical Decision-Making , Humans , Neoplasm Metastasis , Neoplastic Cells, Circulating/metabolism , PrognosisABSTRACT
BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms , Glioblastoma , Mefloquine/administration & dosage , Memantine/administration & dosage , Metformin/administration & dosage , Temozolomide/administration & dosage , Adult , Aged , Brain Neoplasms/diagnosis , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/radiotherapy , Chemotherapy, Adjuvant , Clinical Trials, Phase II as Topic/methods , Female , Glioblastoma/diagnosis , Glioblastoma/drug therapy , Glioblastoma/pathology , Glioblastoma/radiotherapy , Humans , Male , Maximum Tolerated Dose , Mefloquine/adverse effects , Memantine/adverse effects , Metformin/adverse effects , Middle Aged , Progression-Free Survival , Radiotherapy, Adjuvant , Research Design , Temozolomide/adverse effects , Treatment Outcome , Young AdultABSTRACT
Neoplastic leptomeningeal disease (LMD) represents infiltration of the leptomeninges by tumor cells. Knowledge of the frequencies of locations of LMD on MRI may assist in early detection, help elucidate the process of leptomeningeal spread of cancer and understand how LMD affects the central nervous system. Our goal was to identify intracranial sites of neoplastic LMD predilection on MRI in patients with cytologically-proven LMD. The presence of FLAIR signal hyperintensity and T1-weighted post-contrast enhancement in the sulci of the supratentorial compartment and cerebellum and enhancement of the cranial nerves (CNs), basal cisterns, pituitary stalk, and ependymal surface of the lateral ventricles, as well as the presence of parenchymal metastasis were recorded. Within each imaging sequence, sites were ordered by prevalence and compared using McNemar's test. The study included 270 patients. Positive MRI findings were present in 185/270 (68.5%) patients. FLAIR signal hyperintensity was significantly more common (p≤0.003) in the cerebellum (n=96) and occipital lobe (n=92) relative to the other lobes. Leptomeningeal enhancement was also significantly more common (p≤0.009) in the cerebellum (n=82) and occipital lobe (n=67) relative to the other lobes. Enhancement was most commonly found involving CN VII/VIII and the ependymal surface of the lateral ventricles compared to other sites. Parenchymal metastases were present in 110 (40.1%) of the patients. In conclusion, neoplastic LMD predominantly involves the cerebellum and occipital lobes, CN VII/VIII, and the ependymal lining of the lateral ventricles. Parenchymal metastases are frequently present in patients with neoplastic LMD.
Subject(s)
Magnetic Resonance Imaging/methods , Meningeal Carcinomatosis/diagnostic imaging , Meningeal Carcinomatosis/pathology , Neuroimaging/methods , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
Leptomeningeal disease (LMD) represents disseminated intracranial metastatic disease that requires early detection and initiation of therapy. Patients with LMD typically present with a variety of neurologic problems, including ocular disturbances. However, little is reported on LMD presenting exclusively with ocular-related disturbances in the absence of any other central nervous system (CNS) dysfunction. Our goal was to describe the workup for ocular disturbances in the setting of known cancer diagnosis. Retrospective case study utilizing prospectively collected database at a tertiary cancer care center for all patients with diagnosis of LMD between 2001 and 2009. Main outcome was descriptive analysis of ocular findings by primary or admitting service with or without formal ophthalmology exam in workup for LMD. 34 patients demonstrated ocular disturbances without any other CNS manifestations. Our findings demonstrate that 71% of ocular disturbances were detected by the primary admitting services. Formal consultation with ophthalmology resulted in the detection of the remaining cases. The most common findings were cranial nerve deficits, papilledema, and optic disc or retinal infiltration by tumor. These findings supported a further work-up for CNS disease. Therefore, it is appropriate to refer cancer patients with visual complaints or findings on exam to ophthalmology to evaluate for evidence suggestive of LMD that may support a further work-up.
Subject(s)
Cancer Care Facilities , Meningeal Carcinomatosis/complications , Meningeal Carcinomatosis/diagnosis , Tertiary Care Centers , Vision Disorders/diagnosis , Vision Disorders/etiology , Adult , Aged , Diagnosis, Differential , Female , Humans , Male , Meningeal Carcinomatosis/therapy , Middle Aged , Prospective Studies , Retrospective Studies , Tertiary Healthcare/methods , Vision Disorders/therapyABSTRACT
Leptomeningeal metastases (LM) currently lack standardization with respect to response assessment. A Response Assessment in Neuro-Oncology (RANO) working group with expertise in LM developed a consensus proposal for evaluating patients treated for this disease. Three basic elements in assessing response in LM are proposed: a standardized neurological examination, cerebral spinal fluid (CSF) cytology or flow cytometry, and radiographic evaluation. The group recommends that all patients enrolling in clinical trials undergo CSF analysis (cytology in all cancers; flow cytometry in hematologic cancers), complete contrast-enhanced neuraxis MRI, and in instances of planned intra-CSF therapy, radioisotope CSF flow studies. In conjunction with the RANO Neurological Assessment working group, a standardized instrument was created for assessing the neurological exam in patients with LM. Considering that most lesions in LM are nonmeasurable and that assessment of neuroimaging in LM is subjective, neuroimaging is graded as stable, progressive, or improved using a novel radiological LM response scorecard. Radiographic disease progression in isolation (ie, negative CSF cytology/flow cytometry and stable neurological assessment) would be defined as LM disease progression. The RANO LM working group has proposed a method of response evaluation for patients with LM that will require further testing, validation, and likely refinement with use.
Subject(s)
Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/therapy , Clinical Trials as Topic/standards , Disease Progression , Humans , Magnetic Resonance Imaging , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/diagnostic imaging , Treatment OutcomeABSTRACT
OBJECTIVE: Leptomeningeal disease (LMD), the presence of metastasis in the subarachnoid space, has devastating implications if left untreated. The gold standard for LMD diagnosis is cytologic analysis of cerebrospinal fluid (CSF); MRI is also used to evaluate suspected LMD. The purpose of this study was to compare the appearance of LMD in the spinal canal on 18F-FDG PET/CT imaging with the appearance of LMD on MRI and with CSF cytology. METHODS: In twenty-one patients with cytologically-proven spinal LMD, findings on 18F-FDG PET/CT, MRI, and CSF cytology at diagnosis of LMD and after the initiation of treatment for LMD were retrospectively reviewed. RESULTS: At diagnosis of LMD, abnormal 18F-FDG avidity was demonstrated in the spinal canal in six patients, and the anatomic distribution of 18F-FDG activity corresponded to the sites of LMD on MRI. All six of these patients were then treated with intrathecal chemotherapy. Follow-up 18F-FDG PET/CT and MRI were obtained in four of the six cases. In all four cases, normalization of 18F-FDG activity in the spinal canal and reduction of enhancement on MRI corresponded to the cytologic response to treatment, as determined by CSF analysis. CONCLUSION: 18F-FDG avidity in the spinal canal greater than the normal contents of the canal can suggest spinal LMD. This abnormal avidity may be detected before the diagnosis of LMD has been established with MRI or CSF cytology. The spinal canal should be routinely evaluated on 18F-FDG PET/CT in patients with suspected LMD so that appropriate treatment is initiated.
ABSTRACT
BACKGROUND: The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in â¼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results. METHODS: Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation. RESULTS: Progression-free survival at 5.5 months (â¼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy. CONCLUSIONS: This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Cancer Vaccines/therapeutic use , Glioblastoma/drug therapy , Adult , Aged , Aged, 80 and over , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , Chemoradiotherapy, Adjuvant , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Disease-Free Survival , ErbB Receptors/genetics , Female , Glioblastoma/mortality , Glioblastoma/radiotherapy , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Temozolomide , Treatment Outcome , Vaccines, Subunit/therapeutic useABSTRACT
BACKGROUND: Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy. METHODS: The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide. RESULTS: The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia. CONCLUSIONS: The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. CLINICALTRIALSGOV IDENTIFIER: NCT00112502.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/drug therapy , Dacarbazine/analogs & derivatives , Glioblastoma/drug therapy , Isotretinoin/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Thalidomide/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Celecoxib , Chemotherapy, Adjuvant , Dacarbazine/administration & dosage , Dacarbazine/therapeutic use , Disease-Free Survival , Drug Combinations , Female , Humans , Isotretinoin/administration & dosage , Kaplan-Meier Estimate , Male , Middle Aged , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Temozolomide , Thalidomide/administration & dosage , Young AdultABSTRACT
PURPOSE: To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM). METHODS: A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM. RESULTS: A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis. CONCLUSION: Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials.
Subject(s)
Antineoplastic Agents/therapeutic use , Meningeal Neoplasms/drug therapy , Patient Outcome Assessment , Randomized Controlled Trials as Topic/standards , Clinical Trials, Phase II as Topic/standards , Endpoint Determination , Humans , Meningeal Neoplasms/secondary , Treatment OutcomeABSTRACT
BACKGROUND: Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients. METHODS: We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients. RESULTS: Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months. CONCLUSION: Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Glioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Erlotinib Hydrochloride , Female , Follow-Up Studies , Glioma/mortality , Glioma/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Quinazolines/administration & dosage , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , Survival Rate , Tissue Distribution , Young AdultSubject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Papilloma, Choroid Plexus/drug therapy , Adult , Bevacizumab , Brain/pathology , Humans , Lumbar Vertebrae , Male , Middle Aged , Pain Management/methods , Papilloma, Choroid Plexus/pathology , Papilloma, Choroid Plexus/surgery , Spinal Cord/pathologyABSTRACT
BACKGROUND: Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma. METHODS: The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m² daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). RESULTS: Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths. CONCLUSIONS: These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.