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1.
Support Care Cancer ; 30(4): 3463-3471, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35001215

ABSTRACT

PURPOSE: At diagnosis and throughout the disease course, patients with high-grade glioma (HGG) experience a diminished quality of life (QOL) and increased fatigue. Naltrexone, an orally semisynthetic opiate antagonist, is FDA-approved for the treatment of heroin/alcohol addiction, and low-dose naltrexone (LDN) has been observed to improve QOL and lower fatigue in other neurological illnesses, such as multiple sclerosis. LDN is believed to function as a partial agonist and can lead to shifts in neurochemicals that reduce fatigue. Based on this, we sought to study whether LDN has an impact on QOL and fatigue in patients with HGG. METHODS: In a placebo-controlled, double-blind study, we randomized 110 HGG patients to receive placebo (N = 56) or LDN 4.5 mg orally at night (N = 54). Subjects received LDN or placebo at day 1 of concurrent radiation and temozolomide therapy and continued for 16 weeks. Change from baseline in patient-reported outcomes of QOL (Functional Assessment of Cancer Therapy-Brain) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) was assessed. RESULTS: Demographics were WHO grade IV (85%), male (56%), KPS 90-100 (51%), grossly resected (55%), and mean age of 56 years. QOL and fatigue changes between baseline and post concurrent chemotherapy and radiation therapy were not significantly different between patients receiving LDN or placebo. The adverse event profiles for LDN and placebo were similar and attributed to concomitant use of temozolomide. CONCLUSIONS: LDN has no effect on QOL and fatigue in HGG patients during concurrent chemotherapy and radiation therapy. TRIAL REGISTRATION: United States National Library of Medicine Clinical Trials.gov NCT01303835, Date 2/25/2011.


Subject(s)
Glioma , Quality of Life , Double-Blind Method , Glioma/drug therapy , Glioma/radiotherapy , Humans , Male , Middle Aged , Naltrexone , Temozolomide
2.
N Engl J Med ; 379(2): 150-161, 2018 07 12.
Article in English | MEDLINE | ID: mdl-29943666

ABSTRACT

BACKGROUND: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. METHODS: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase. RESULTS: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. CONCLUSIONS: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).


Subject(s)
Glioblastoma/therapy , Immunotherapy , Neoplasm Recurrence, Local/therapy , Oncolytic Virotherapy , Poliovirus , Rhinovirus , Adult , Aged , Chimera , Female , Glioblastoma/mortality , Humans , Infusions, Intralesional , Male , Middle Aged , Survival Rate , Young Adult
3.
Nature ; 519(7543): 366-9, 2015 Mar 19.
Article in English | MEDLINE | ID: mdl-25762141

ABSTRACT

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.


Subject(s)
Cancer Vaccines/immunology , Chemokine CCL3/immunology , Dendritic Cells/drug effects , Glioblastoma/immunology , Glioblastoma/therapy , Tetanus Toxoid/administration & dosage , Tetanus Toxoid/pharmacology , Animals , Antigens, Neoplasm/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/therapeutic use , Cell Movement/drug effects , Dendritic Cells/cytology , Dendritic Cells/immunology , Female , Glioblastoma/drug therapy , Glioblastoma/pathology , Humans , Immunotherapy/methods , Lymph Nodes/cytology , Lymph Nodes/drug effects , Lymph Nodes/immunology , Mice , Mice, Inbred C57BL , Phosphoproteins/chemistry , Phosphoproteins/genetics , Phosphoproteins/immunology , Substrate Specificity , Survival Rate , Tetanus Toxoid/therapeutic use , Treatment Outcome , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/genetics , Viral Matrix Proteins/immunology
4.
Invest New Drugs ; 38(6): 1784-1795, 2020 12.
Article in English | MEDLINE | ID: mdl-32436060

ABSTRACT

Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF-06840002 was 1.5-3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (< 1%). At 500 mg BID, maximum mean percentage inhibition of 13C10 kynurenine vs endogenous kynurenine was 75% vs 24%. PF-06840002 CSF-to-plasma ratio was 1.00. Disease control occurred in eight patients (47%). Mean duration of stable disease (SD) was 32.1 (12.1-72.3) weeks. Two patients with SD discontinued the study at 450 and 561 days and continued PF-06840003 on compassionate use. Conclusion PF­06840003 up to 500 mg BID was generally well tolerated with evidence of a pharmacodynamic effect and durable clinical benefit in a subset of patients with recurrent malignant glioma. ClinicalTrials.gov, NCT02764151, registered April 2016.


Subject(s)
Antineoplastic Agents/administration & dosage , Central Nervous System Neoplasms/drug therapy , Glioma/drug therapy , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoles/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Succinimides/administration & dosage , Adolescent , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Female , Humans , Indoles/adverse effects , Indoles/pharmacokinetics , Kynurenine/metabolism , Male , Middle Aged , Succinimides/adverse effects , Succinimides/pharmacokinetics , Treatment Outcome , Tryptophan/metabolism , Young Adult
5.
Invest New Drugs ; 38(5): 1570-1579, 2020 10.
Article in English | MEDLINE | ID: mdl-32140889

ABSTRACT

Purpose Galunisertib, a TGF-ß inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.


Subject(s)
Antineoplastic Agents/administration & dosage , Brain Neoplasms/therapy , Chemoradiotherapy , Glioma/therapy , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Quinolines/administration & dosage , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , Temozolomide/administration & dosage , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/metabolism , Brain Neoplasms/immunology , Brain Neoplasms/metabolism , Female , Glioma/immunology , Glioma/metabolism , Humans , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Quinolines/adverse effects , T-Lymphocyte Subsets/drug effects , Temozolomide/adverse effects
6.
J Neurooncol ; 147(2): 477-483, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32140975

ABSTRACT

PURPOSE: Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin's lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~ 3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed. METHODS: This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. We retrospectively identified all cases of PCNSL as part of a database registry and evaluated these cases for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median relapse-free survival. RESULTS: This analysis identified 44 patients with a pathologically confirmed diagnosis of PCNSL. Mean age at diagnosis was 63.1 years (range 20-86, SD = 13.2 years). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity that required a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n = 5), vitreous fluid only (n = 1), outside CNS only (n = 3), or a combination of CNS and outside of the CNS (n = 2). Sites of relapse outside of the CNS included testes (n = 1), lung (n = 1), adrenal gland (n = 1), kidney/adrenal gland (n = 1), and retroperitoneum (n = 1). Median relapse-free survival after successful completion of therapy was 6.7 years (95% CI 1.1, 12.6). CONCLUSION: After successful initial treatment, PCNSL has a propensity to relapse, and this relapse can occur both inside and outside of the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/drug therapy , Induction Chemotherapy/mortality , Lymphoma, Non-Hodgkin/drug therapy , Neoplasm Recurrence, Local/epidemiology , Adult , Aged , Aged, 80 and over , Central Nervous System Neoplasms/pathology , Female , Follow-Up Studies , Humans , Lymphoma, Non-Hodgkin/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , North Carolina/epidemiology , Prognosis , Retrospective Studies , Survival Rate , Young Adult
7.
Support Care Cancer ; 28(5): 2229-2238, 2020 May.
Article in English | MEDLINE | ID: mdl-31440823

ABSTRACT

PURPOSE: CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. METHODS: One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200 mg/m2/day × 5 days every 28 days) were randomized to Arm-A (ondansetron 8 mg days 1-5 with aprepitant day 1: 125 mg, days 2-5: 80 mg) or Arm-B (ondansetron). Randomization was stratified by tumor grade and number of prior chemotherapy regimens. The primary endpoint was the percentage of patients achieving complete control (CC), defined as no emetic episode or antiemetic rescue medication over the 7-day study period. Secondary endpoints included CINV efficacy in the acute phase (≤ 24 h) and delayed phase (days 2-7), as well as safety and quality of life (QoL). RESULTS: Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity. CONCLUSIONS: Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV's effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.


Subject(s)
Aprepitant/therapeutic use , Brain Neoplasms/drug therapy , Glioma/drug therapy , Nausea/prevention & control , Ondansetron/therapeutic use , Temozolomide/adverse effects , Vomiting/prevention & control , Adult , Aged , Antiemetics/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Female , Humans , Male , Middle Aged , Nausea/chemically induced , Quality of Life , Temozolomide/therapeutic use , Vomiting/chemically induced
8.
Oncologist ; 23(8): 889-e98, 2018 08.
Article in English | MEDLINE | ID: mdl-29666296

ABSTRACT

LESSONS LEARNED: Due to evolving imaging criteria in brain tumors and variation in magnetic resonance imaging evaluation, it is not ideal to use response rate as a primary objective. Future studies involving antiangiogenic agents should use overall survival.Disease-expected toxicities should be considered when defining the clinical significance of an adverse event. For example, vascular thromboembolic events are common in brain tumor patients and should not be attributed to the study drug in the safety analysis. BACKGROUND: Recurrent malignant glioma (rMG) prognosis is poor, with a median patient survival of 3-11 months with bevacizumab (BEV)-containing regimens. BEV in rMG has 6-month progression free survival (PFS-6) of ∼40% and an objective response rate of 21.2%. BEV-containing regimens improve PFS-6 to 42.6%-50.3%, indicating that BEV combination therapies may be superior to single agent. Rilotumumab, a hepatocyte growth factor (HGF) antibody, inhibits angiogenesis and expression of angiogenic autocrine factors (e.g., vascular endothelial growth factor [VEGF]) by c-Met inhibition. Combination of rilotumumab with BEV to block vascular invasion and tumor proliferation may synergistically inhibit tumor growth. METHODS: Thirty-six BEV-naïve rMG subjects received rilotumumab (20 mg/kg and BEV (10 mg/kg) every 2 weeks. Endpoints included objective response rate (using Response Assessment in Neuro-Oncology [RANO] criteria), PFS-6, overall survival (OS), and toxicity. RESULTS: Median patient follow-up was 65.0 months. Objective response rate was 27.8% (95% confidence interval [CI]: 15.7%-44.1%). Median OS was 11.2 months (95% CI: 7-17.5). PFS-6 was 41.7% (95% CI: 25.6%-57.0%). Most frequent treatment-related grade ≤2 events included weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥3 events included venous thromboembolism (four patients), including one death from pulmonary embolism. CONCLUSION: Rilotumumab with BEV did not significantly improve objective response compared with BEV alone, and toxicity may preclude the use of rilotumumab in combination BEV regimens.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Bevacizumab/therapeutic use , Glioma/drug therapy , Adult , Aged , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Bevacizumab/pharmacology , Female , Glioma/pathology , Humans , Male , Middle Aged
9.
Oncologist ; 23(2): 157-e21, 2018 02.
Article in English | MEDLINE | ID: mdl-29133513

ABSTRACT

LESSONS LEARNED: Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens. BACKGROUND: Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression-free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM. MATERIALS AND METHODS: In this phase II, single-center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28-day cycle. The primary endpoint was 6-month PFS (PFS6). RESULTS: Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%-44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6-12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment-related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified. CONCLUSION: Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Glioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Bevacizumab/administration & dosage , Brain Neoplasms/pathology , Female , Follow-Up Studies , Glioma/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Non-Randomized Controlled Trials as Topic , Prognosis , Survival Rate , Vorinostat/administration & dosage , World Health Organization
10.
J Neurooncol ; 137(2): 349-356, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29264836

ABSTRACT

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m2 po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2-67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.


Subject(s)
Antineoplastic Agents/therapeutic use , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Glioma/drug therapy , Temozolomide/therapeutic use , Vorinostat/therapeutic use , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols , Bevacizumab/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Survival Analysis , Temozolomide/adverse effects , Treatment Outcome , Vorinostat/adverse effects
11.
J Neurooncol ; 138(3): 489-498, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29564747

ABSTRACT

BACKGROUND: Sym004 is a mixture of two monoclonal antibodies (mAbs), futuximab and modotuximab, targeting non-overlapping epitopes on the epidermal growth factor receptor (EGFR). Previous studies have shown that Sym004 is more efficient at inducing internalization and degradation of EGFR than individual components, which translates into superior cancer cell inhibition. We investigated whether Sym004 induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII). METHODS: To address this question, we tested the effect of Sym004 versus cetuximab in eight patient-derived GBM xenograft models expressing either wild-type EGFR (EGFRwt) and/or mutant EGFRvIII. All models were tested as both subcutaneous and orthotopic intracranial xenograft models. RESULTS: In vitro studies demonstrated that Sym004 internalized and removed EGFRvIII more efficiently than mAbs, futuximab, modotuximab, and cetuximab. Removal of EGFRvIII by Sym004 translated into significant in vivo anti-tumor activity in all six EGFRvIII xenograft models. Furthermore, the anti-tumor activity of Sym004 in vivo was superior to that of its individual components, futuximab and modotuximab, suggesting a clear synergistic effect of the mAbs in the mixture. CONCLUSION: These results demonstrate the broad activity of Sym004 in patient-derived EGFRvIII-expressing GBM xenograft models and provide a clear rationale for clinical evaluation of Sym004 in EGFRvIII-positive adult GBM patients.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Brain Neoplasms/therapy , Glioblastoma/therapy , Animals , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , ErbB Receptors/genetics , ErbB Receptors/immunology , ErbB Receptors/metabolism , Female , Glioblastoma/genetics , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Male , Mice, Inbred BALB C , Mice, Nude , Subcutaneous Tissue , Xenograft Model Antitumor Assays
12.
J Neurooncol ; 134(2): 363-369, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28669010

ABSTRACT

Primary brain tumor patients experience high levels of distress. The purpose of this cross-sectional, retrospective study is to evaluate the level and different sources of psychosocial distress and how these pertain to health-related quality of life (HRQoL). The Primary and Recurrent Glioma registry at Duke's The Preston Robert Tisch Brain Tumor Center was queried retrospectively for demographic and clinical information on patients seen between December 2013 and February 2014. Data also included the National Comprehensive Cancer Network's Distress Thermometer (NCCN-DT), Functional Assessment of Cancer Therapy-Brain Cancer (FACT-Br), and Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). 829 subjects completed questionnaires. 54% were male; 96% completed the NCCN-DT; 33.3% had a DT score ≥4 (moderate/severe distress). Women reported DT ≥ 4 more often than men (38.6 vs 29.0%; p = 0.005). Patients within 1 year of diagnosis reported DT ≥ 4 more often than those 1+ years after diagnosis (38.8 vs 30.9%; p = 0.034). 73.0% reported physical problems; the most frequent being fatigue (43.2%) and memory/concentration (40.9%). 42.0% complained of emotional problems with worry (29.4%) and nervousness (22.4%) being the most common. Patients who reported at least one practical, family, emotional or physical problem had significantly lower HRQoL scores (p < 0.001). Primary brain tumor patients experience memory dysfunction, fatigue, nervousness, worry, and financial concerns, which have a negative effect on the patient's HRQoL. By identifying and addressing these stressors, it may be possible to improve patient HRQoL.


Subject(s)
Brain Neoplasms/psychology , Quality of Life , Stress, Psychological , Adolescent , Adult , Aged , Aged, 80 and over , Brain Neoplasms/complications , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Registries , Retrospective Studies , Sex Factors , Stress, Psychological/epidemiology , Surveys and Questionnaires , Time Factors , Young Adult
13.
Cancer ; 122(4): 582-7, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26588662

ABSTRACT

BACKGROUND: Cabozantinib inhibits mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and has demonstrated activity in patients with recurrent glioblastoma, warranting evaluation of the addition of cabozantinib to radiotherapy (RT) and temozolomide (TMZ) for patients with newly diagnosed high-grade glioma. METHODS: Cabozantinib doses of 40 mg and 60 mg were explored. Patients on the concurrent treatment arm received cabozantinib daily with standard TMZ and after RT continued cabozantinib daily with adjuvant TMZ. In the maintenance arm, patients who completed RT and ≥1 adjuvant cycle of TMZ continued adjuvant TMZ with added cabozantinib (3 schedules: days 1-28, days 1-14, or days 8-21). RESULTS: A total of 26 patients (25 with recurrent glioblastoma and 1 patient with anaplastic astrocytoma) aged 30 to 72 years were enrolled (10 to the concurrent arm and 16 to the maintenance arm). The median number of post-RT TMZ cycles was 4.5 (range, 0-14 cycles) in the concurrent arm and 5.5 (range, 1-12 cycles) in the maintenance arm. Cabozantinib at a dose of 60 mg daily was the maximum administered dose and a dose of 40 mg daily was determined to be the maximum tolerated dose for both treatment arms (schedule of days 1-28). The most frequent grade 3/4 adverse events were thrombocytopenia (31% of patients), leukopenia (27% of patients, including 5 patients with neutropenia), and deep vein thrombosis and/or pulmonary embolism (23% of patients) (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). CONCLUSIONS: Cabozantinib at a dose of 40 mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40 mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Astrocytoma/therapy , Brain Neoplasms/therapy , Glioblastoma/therapy , Adult , Aged , Alanine Transaminase/blood , Anilides/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aspartate Aminotransferases/blood , Astrocytoma/pathology , Brain Neoplasms/pathology , Chemoradiotherapy/methods , Chemoradiotherapy, Adjuvant/methods , Constipation/chemically induced , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Diarrhea , Fatigue/chemically induced , Female , Glioblastoma/pathology , Humans , Hypertension/chemically induced , L-Lactate Dehydrogenase/blood , Leukopenia , Maintenance Chemotherapy/methods , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Neoplasm Grading , Neurosurgical Procedures , Neutropenia , Pyridines/administration & dosage , Temozolomide , Thrombocytopenia/chemically induced , Treatment Outcome
14.
Oncology (Williston Park) ; 30(3): 211-8, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26984213

ABSTRACT

After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary.


Subject(s)
Cancer Vaccines/pharmacology , Glioma/therapy , Immunotherapy, Active , Oncolytic Virotherapy , Oncolytic Viruses/metabolism , Antineoplastic Agents/pharmacology , Humans , Immune Tolerance/drug effects , Immunotherapy, Active/adverse effects , Immunotherapy, Active/methods , Oncolytic Virotherapy/adverse effects , Oncolytic Virotherapy/methods
15.
Support Care Cancer ; 24(10): 4365-75, 2016 10.
Article in English | MEDLINE | ID: mdl-27271867

ABSTRACT

BACKGROUND: In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control. METHODS: We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54-60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m(2)/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. RESULTS: We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67-79 %. CONCLUSION: Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.


Subject(s)
Antineoplastic Agents/therapeutic use , Chemoradiotherapy/methods , Dacarbazine/analogs & derivatives , Glioma/drug therapy , Glioma/radiotherapy , Isoquinolines/therapeutic use , Quality of Life/psychology , Quinuclidines/therapeutic use , Administration, Intravenous , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Dacarbazine/adverse effects , Dacarbazine/pharmacology , Dacarbazine/therapeutic use , Female , Glioma/pathology , Humans , Isoquinolines/adverse effects , Isoquinolines/pharmacology , Male , Middle Aged , Palonosetron , Quinuclidines/adverse effects , Quinuclidines/pharmacology , Surveys and Questionnaires , Temozolomide
16.
Oncologist ; 20(7): 727-8, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26025933

ABSTRACT

LESSONS LEARNED: Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. BACKGROUND: Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. METHODS: Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. RESULTS: Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months). CONCLUSION: Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Bevacizumab/administration & dosage , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , Brain Neoplasms/surgery , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Drug Administration Schedule , Female , Glioblastoma/mortality , Glioblastoma/radiotherapy , Glioblastoma/surgery , Humans , Irinotecan , Male , Middle Aged , Temozolomide , Treatment Outcome
17.
Cancer ; 120(21): 3277-86, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-24939611

ABSTRACT

Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.


Subject(s)
Immunity, Innate/genetics , Neoplasms/genetics , Neoplasms/therapy , Oncolytic Virotherapy , Oncolytic Viruses/genetics , Humans , Immunotherapy , Neoplasms/virology , Poliomyelitis/genetics , Receptors, Virus/immunology , Virus Internalization
18.
J Neurooncol ; 120(3): 499-506, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25115739

ABSTRACT

Quality of life (QoL) impairment and fatigue are frequently experienced during treatment for recurrent high-grade glioma (HGG). Fatigue and QoL impairments can be due to primary neurological dysfunction, cytotoxic treatments, mood disturbances, and supportive medications. We now seek to understand how QoL and fatigue impacts survival in recurrent HGG. Using a prospective observational design, 237 patients with recurrent HGG and KPS ≥70 completed a self-administered questionnaire that evaluated QoL and fatigue. QoL was assessed with Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Brain (FACT-Br) scales while fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT-F) scale. Cox proportional hazard models were utilized to evaluate the association between QoL and fatigue and survival. Seventy-three (31 %) subjects had recurrent WHO grade III gliomas and 164 (69 %) had recurrent WHO grade IV gliomas. Median follow-up analysis was 27.60 months. In univariate Cox analyses, the FACT-Br specific subscale (HR 0.88; CI 95 %, 0.77-1; p = 0.048) and FACIT-F (HR 0.82; CI 95 %, 0.68-0.99; p = 0.045) were both significant predictors of survival. Fatigue added prognostic information beyond that provided by KPS, age, sex, tumor grade, and number of prior progressions (HR 0.80; CI 95 %, 0.68-0.9; p = 0.031). A greater degree of fatigue was associated with poorer survival in recurrent HGG patients. In multivariable analyses, FACT-G and FACT-Br are not independent predictors of prognosis. Fatigue is a strong independent predictor of survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent HGG. Pharmacological or non-pharmacological strategies to treat fatigue warrant investigation.


Subject(s)
Brain Neoplasms/mortality , Brain Neoplasms/psychology , Fatigue/etiology , Glioma/mortality , Glioma/psychology , Quality of Life , Adult , Aged , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Fatigue/psychology , Female , Follow-Up Studies , Glioma/pathology , Glioma/therapy , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local , Prognosis , Proportional Hazards Models , Prospective Studies , Salvage Therapy , Surveys and Questionnaires , Young Adult
19.
Neurooncol Pract ; 11(2): 199-204, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38496920

ABSTRACT

Background: Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020. Methods: Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily. Results: The cohort age range was 21-74 years. Tumor types included astrocytoma (n = 14) and oligodendroglioma (n = 16), with most being grade 2 (n = 21). The best radiographic response in nonenhancing disease (n = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, n = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Conclusions: Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes.

20.
Nat Commun ; 15(1): 6870, 2024 Aug 11.
Article in English | MEDLINE | ID: mdl-39127809

ABSTRACT

Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0-36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.


Subject(s)
Brain Neoplasms , Cancer Vaccines , Glioblastoma , Precision Medicine , Protein Subunit Vaccines , Adult , Aged , Female , Humans , Male , Middle Aged , Antigens, Neoplasm/immunology , Brain Neoplasms/immunology , Brain Neoplasms/therapy , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Glioblastoma/immunology , Glioblastoma/therapy , Precision Medicine/methods , Protein Subunit Vaccines/immunology , Protein Subunit Vaccines/therapeutic use , T-Lymphocytes/immunology , Treatment Outcome
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