Anaplastic astrocytomas: biology and treatment Chamberlain, Marc C; Chowdhary, Sajeel A; Glantz, Michael J
Expert review of neurotherapeutics,
20/4/1/, Letnik:
8, Številka:
4
Journal Article
Recenzirano
Anaplastic astrocytomas (AA), WHO grade III gliomas, comprise 10-15% of all glial neoplasms. Currently, the only factors that have been shown to influence prognosis in patients with AA are age and ...Karnofsky performance status. Attempts have been made to identify biological prognostic factors for response to therapy and clinical outcome, as well as potential targets for new therapies. The most important predictor of response to therapy and survival in AA tumors is the presence or absence of the 1p19q co-deletion, a translocation that defines a subset of oligodendroglial tumors, and anaplastic oligodendrogliomas in particular. A further likely prognostic biomarker is the methylation status of O
6
-methylguanine-DNA-methyltranferase gene (the predominant DNA repair enzyme following alkylator-based chemotherapy-induced injury). Owing to a paucity of clinical trials specifically in patients with AA, most patients receive temozolomide-containing regimens, based on data acquired from patients with glioblastoma multiforme. At present, there are no cooperative group trials being conducted for the adjuvant treatment of AA, although several randomized trials have been proposed. Evidence-based management of patients with AA supports maximum safe resection followed by involved-field radiotherapy for newly diagnosed patients, and temozolomide for recurrent disease. This treatment paradigm varies considerably from actual practice.
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2513
Background: MDNA55 is an engineered IL-4 fused to pseudomonas exotoxin A being developed for GBM, an aggressive, universally fatal disease. No curative therapy exists and 75% of ...patients are not eligible for resection at recurrence. MDNA55 targets IL4R overexpressed in GBM, the immunosuppressive tumor microenvironment, and high expression is associated with poor survival outcomes in GBM. A Ph 2b trial of MDNA55 was completed in rGBM using convection-enhanced delivery to bypass the BBB. Here we report results from the Ph 2b trial and comparison against a matched Synthetic Control Arm (SCA). Methods: MDNA55-05 is an open-label, single-arm study of intratumoral delivery of ≤ 240 μg MDNA55 as a single treatment via ≤ 4 catheters in de novo GBM without IDH1/2 mutation at 1st or 2nd recurrence not eligible for resection, tumors ≤ 4 cm, KPS ≥ 70. IL4R expression in GBM tissues was determined by H-Score using a validated IHC assay. 1
o
endpoint is median overall survival (mOS); 2
o
endpoint includes the impact of IL4R status on mOS. An eligibility-matched SCA was identified retrospectively from patient registries at major neurosurgery centers with access to GBM tumor tissue banks under IRB-approved protocols. Results: 44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide. Conclusions: MDNA55 subjects represent a difficult to treat population ( de novo GBM, IDH wild-type, not eligible for surgery at recurrence). Single treatment with MDNA55 prolongs survival by nearly 10 months in a subset of rGBM expressing high levels of IL4R when compared to a matched SCA, providing an unprecedented outcome for this highly lethal disease. Clinical trial information: NCT02858895 .
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2502
Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate ...benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided >79% power to detect a PFS6 rate >65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided >94% power to detect RR >20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014 .
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2039
Background: IL4 receptor (IL4R) is frequently and intensely expressed on a variety of human cancers and is associated with poor survival outcomes. Determining the role of the IL4R ...biomarker in glioblastoma (GBM) will be important for treatment with targeted therapies such as the IL4 fusion toxin MDNA55. Methods: A classification for IL4Rα expression in GBM tissues by H-Score was developed using a validated immunohistochemistry-based approach. MDNA55-05 is an open-label study of MDNA55 administered intratumorally via convection enhanced delivery in recurrent GBM. Levels of IL4Rα expression were assessed retrospectively in 24 subjects in the clinical trial and were correlated with GBM history, imaging responses and survival outcomes following treatment with MDNA55 to explore clinical validation. Results: Range, linearity, specificity and sensitivity testing using a rabbit polyclonal antibody to IL4Rα were performed using normal cortex (negative control) and a panel of normal human tissues and GBM cases from tissue banks. A total of 41 GBM samples were screened and grouped by reactivity thresholds: H-Scores ≥50 were observed in 95% of cases (39/41), H-Scores ≥200 were observed in 51% of cases (21/41), and H-Scores ≥250 were observed in 24% of cases (10/41). GBM tissues obtained at initial diagnosis from subjects enrolled in the trial show that moderate/high IL4R expression (H-Score > 75) was associated with shorter time to first relapse when compared to subjects with low IL4R expression (H-Score ≤ 75) (10.3 mos vs. 16.7 mos, respectively) after upfront standard-of-care treatment, consistent with published findings that IL4R expression is associated with more aggressive disease. Remarkable decreases in tumor size seen in some subjects following MDNA55 treatment were associated only with moderate/high IL4R expression and survival rate at 12 months in this group was also improved (OS12 = 55%) compared to subjects with low IL4R expression (OS12 = 30%). Conclusions: Treatment options for patients with recurrent GBM are very limited and positive outcomes remain rare. Targeting therapies such as MDNA55 by IL4R status may improve patient outcomes and help guide patient selection strategies for future clinical studies. Clinical trial information: NCT02858895.
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e12500
Background: This STTR Phase 1 study focused on enhancing and improving the technology of a prior AVR system (Grant #R01 CA30724) to manage symptoms in cancer patients. ...Neuro-Oncology patients were enrolled to test our proof of concept (POC). Methods: Previous AVR function was replicated using Asterisk software enhancing the branching logic, configurability and operational capacity on multiple operating systems; limitations of the previous AVR. Eligibility criteria: access to a telephone; actively on chemotherapy. Nurse recruiters provided detailed information about the study and answered questions. Following signed consent patients provided a preferred phone number and chose a day and time of the week to receive AVR calls. Patients received a Symptom Management Guide (SMG) at time of consent. Patients were contacted a total of 4 times over a 4 week period by the AVR. At each contact patients were asked to rate 17 symptoms on a scale of 1-9 for severity and interference with 4 domains of quality of life on a 1-5 scale. Patient’s reporting a 4 or higher severity level were directed by the AVR to reference their SMG for self-care strategies to manage their symptoms. At the end of the study patients completed a satisfaction survey. Results: Ten patients were enrolled. The AVR placed 38 of 40 scheduled calls. No errors in survey branching were evident with confirmation. Patient satisfaction surveys were completed with 70% of patients. One patient did not complete any scheduled calls and was not contacted, two patients were unreachable. All patients reported satisfaction. 86% reported they would recommend this system to their oncology provider. 71% felt it was helpful in individualized monitoring of symptoms between visits. 57% liked knowing their symptom(s) were being checked regularly. One indicated the system was too overwhelming. Complaints included: not being able to change responses (1) and not allowing them to answer questions as fast as they wanted (2). Conclusions: Patient satisfaction results and system performance confirmed that the POC was feasible and that this system should be studied in larger groups of oncology patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
18.
Cancer in the Spine: Comprehensive Care Vrionis, Frank D.; Chowdhary, Sajeel A.
Neuro-oncology (Charlottesville, Va.),
07/2006, Letnik:
8, Številka:
3
Journal Article
AT-101 is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of the parent compound, racemic gossypol, demonstrated ...objective and durable responses in patients with malignant glioma. AT-101 has demonstrated synergy with radiation in animal models. The objectives of trial NABTT 0602 were to determine the MTD of AT-101 concurrent with temozolomide (TMZ) and radiation therapy (RT) (Arm I) and to determine the MTD of AT-101 when given with adjuvant TMZ after completion of standard chemoradiation (Arm 2). Separately in trial NABTT 0702, the survival and response rates of single agent AT-101 were evaluated in patients with recurrent glioblastoma.
In NABTT 0602 Phase I, a 3+3 design was used to define MTDs after maximal safe resection, patients with newly diagnosed glioblastoma received standard concurrent RT (60 Gy) and TMZ 75 mg/m2/day followed by adjuvant TMZ 150-200 mg/m2 days 1-5 in 28-day cycles (Stupp regimen). In Arm I, AT-101 was administered M-F during the six weeks of RT beginning 20 mg qd. In Arm 2, concurrent with each adjuvant cycle of TMZ, AT-101 was administered at a starting dose of 20 mg, days 1-21 followed by 7-day break for a maximum of 6 cycles. The PK blood samples were collected in the first three patients in each cohort of arm 1. In NABTT 0702 patients with recurrent glioblastoma received 20 mg p.o. per day for 21 of 28 days in repeated cycles to assess overall survival (OS).
A total of sixteen patients were enrolled on the two study arms of NABTT 0602. In Arm 1 AT-101 was escalated from 20 to 30 mg where one of six patients experienced DLT (grade 3 GI ulcer). On Arm 2 one patient treated at 20 mg experienced DLT (grade 3 ileus, nausea and diarrhea). The cohort was expanded to include seven patients without observation of DLT. PK results were consistent with drug levels from non-CNS studies. At study closure six patients are still alive. The median survival times for Arm I and Arm II are 15.2 months and 18.2 months, respectively. In NABTT 0702 fifty-six patients were enrolled and forty-three were eligible for imaging response. Sixteen patients (29%) had stable disease as best response and one partial response was observed. The median OS with single agent AT-101 was 5.7 months (95%CI: 3.8-7.6 months) for patients with rGBM.
AT-101 can be safely administered with radiation therapy and TMZ in patients with newly diagnosed glioblastoma without toxicity unique to patients with CNS tumors. Because of toxicity observed in non-CNS AT-101 clinical trials, further dose-escalation was not attempted. The recommended dose for future studies that utilize continual AT-101 exposure is 20 mg days M-F concurrent with RT/TMZ and 20 mg days 1-21 for each 28-day cycle of TMZ. AT-101 has limited activity as a single agent in unselected patients with recurrent glioblastoma. Future trials should attempt to better understand resistance mechanisms and consider combination therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glioblastoma (GB) is the most common adult malignant primary brain tumor that arises from glial precursor cells. Survival in GB is variable ranging from 6 to 20 months notwithstanding current ...standard of care (SOC) treatment. Therapy has improved, but nonetheless GB is still invariably recurrent and incurable. Treatment options at recurrence include re-operation with or without carmustine (BCNU) wafer implantation (Gliadel), re-irradiation and standard/experimental chemo- or targeted therapy. Recurrent GB radiographic response rates to cytotoxic chemotherapy are less than 10% and median 6-month progression-free survival (PFS6) is 15%. With the recognition of the importance of tumor angiogenesis and the development of targeted therapy based on angiogenic inhibition, two pivotal trials of the VEGF-directed monoclonal antibody, bevacizumab (BEV, Avastin), were conducted in recurrent GB. Based upon the results of these two prospective US trials (median radiographic response rate: 25%; PFS6: 40%), BEV as a single agent was granted accelerated approval in the USA for recurrent GB. This review is a summary of current literature and clinical trials research in the role of BEV for the treatment of newly diagnosed and recurrent GB and potential future use of anti-angiogenic therapies in the management of GB.
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