Example personalized tumor board report with precision medicine trial regimen recommendations.

Purpose: Existing salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with a median survival of approximately 9 months. Given the complex molecular heterogeneity of GBM, single-target approaches have consistently failed as a treatment strategy. We conducted a phase I clinical trial to assess the feasibility, safety, and efficacy of a genomically tailored multiagent regimen in 30 adults with surgically treated rGBM.Patients and Methods: Adults with IDH wild-type GBM (n = 29) or grade 4 IDH-mutant astrocytoma (n = 1) were consented and underwent clinically indicated surgery for recurrent disease. Comprehensive genomic profiling was performed on the recurrent tumors, and results for each patient were discussed at an individualized molecular tumor board to determine a personalized treatment regimen combining up to four FDA-approved drugs, including one cytotoxic agent as the backbone.Results: A total of 12 drugs were used in 18 combinations-the most common regimen was lomustine, afatinib, and abemaciclib (n = 8). The most common toxicities included cytopenias, rash, and gastrointestinal symptoms, requiring frequent dose reductions. Measured from surgery at trial enrollment, progression-free survival at 6 months was 40%, overall survival (OS) at 9 months was 73%, and median OS was 12.7 months. After trial therapy, genomic profiling performed on subsequent recurrent tumor specimens identified genetic evolution corresponding to putative treatment resistance mechanisms.Conclusions: Implementation of individualized treatment regimens in a timely fashion was feasible for patients with surgically resectable rGBM. Overall efficacy was not significantly improved compared with a contemporary patient cohort treated without experimental regimens, with full dosing of most combination therapies limited by toxicities.

Abstract Salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median overall survival of 9 months (OS-9) and 6-month progression-free survival (PFS-6) of 10-25%. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. An initial 15-patient cohort evaluated the feasibility and safety of treating patients with rGBM with an individualized treatment regimen; we added a second 15-patient expansion cohort to improve the power of preliminary efficacy assessment. Patients underwent clinically indicated surgery with genomic profiling using the UCSF500 targeted DNA sequencing panel. Each personalized treatment regimen combined up to 4 FDA-approved drugs, including one cytotoxic agent, as determined by consensus discussion at an individualized molecular tumor board for each patient. Bevacizumab was not utilized in these combinations. The primary objective of the combined 30-patient cohort was efficacy of individualized treatment regimens by OS-9; secondary objectives included safety and additional efficacy measures including PFS-6. Median age was 53 years (range 32-71). Of 30 patients, 18 were male, 23 were enrolled at first recurrence, 29 had IDH-wildtype glioblastoma, 1 had IDH-mutant astrocytoma, and 10 had MGMT promoter methylation. A total of 12 FDA-approved drugs were used in 18 combinations; the most common regimen prescribed was lomustine, afatinib, and abemaciclib (7; 23%,); second-most common was temozolomide, olaparib, and afatinib (4; 13%). OS-9 of the combined cohort was 70% (95% CI 0.55 – 0.89) and PFS-6 was 27% (95% CI 0.15 – 0.48), with median OS of 11.6 months (95% CI 9.7 – 16.7) and median PFS of 3.7 months (95% CI 2.0 – 5.5).While overall efficacy was modest, implementation of individualized treatment regimens in a timely fashion was safe and feasible for patients with surgically resectable rGBM. Analysis is ongoing to assess whether specific genomic profiles or treatment regimens were particularly efficacious.

Abstract Recurrence of higher-grade meningioma after initial resection and radiotherapy is frequent and associated with high rates of morbidity and mortality. Salvage therapies have limited efficacy and average survival after recurrence is approximately 5-10 years. We report here preliminary data from a phase 2 study combining immunotherapy with checkpoint inhibition with stereotactic radiosurgery for treatment of recurrent high-grade meningioma (NCT04659811). Adult patients with either grade 2 or 3 meningioma who have recurred despite treatment with surgery and radiation and who meet eligibility criteria received stereotactic radiosurgery, in 1 to 5 fractions, in conjunction with pembrolizumab 200mg on the first day of radiation and then every 3 weeks until progression, unacceptable toxicity or for 2 years. Primary objective is PFS12, and secondary objectives include safety of the combined treatment in recurrent meningioma, mOS, mPFS, and neurocognitive function and QOL metrics. To date we have enrolled 18 of planned 37 patients, 33% female, 39% grade 2 and 61% grade 3. Safety lead in was completed without any dose limiting toxicity. There have been 4 SAEs, only one of which was related to study treatment (cerebral edema). 29% of patients had at least one AE, the most common were GI disorders (23%), skin disorders (23%) and headache (17%). Preliminary data from 12 patients shows PFS12 to be 50%, which suggests that the combination of stereotactic radiosurgery may be more beneficial than treatment of Pembrolizumab alone (mPFS 7.6 months). One patient was found to have a homozygous focal deletion of the MLH1 gene and had a dramatic reduction in size of her meningioma with a durable response for over one year. These preliminary data suggest that the combination of stereotactic radiosurgery and pembrolizumab is safe, well tolerated and may be beneficial to patients with recurrent higher-grade meningioma.

Background: Central nervous system (CNS) WHO grade 2 low-grade glioma (LGG) patients are at high risk for recurrence and with unfavorable long-term prognosis due to the treatment resistance and malignant transformation to high-grade glioma. Considering the relatively intact systemic immunity and slow-growing nature, immunotherapy may offer an effective treatment option for LGG patients.Methods: We conducted a prospective, randomized pilot study to evaluate the safety and immunological response of the multipeptide IMA950 vaccine with agonistic anti-CD27 antibody, varlilumab, in CNS WHO grade 2 LGG patients. Patients were randomized to receive combination therapy with IMA950 + poly-ICLC and varlilumab (Arm 1) or IMA950 + poly-ICLC (Arm 2) before surgery, followed by adjuvant vaccines.Results: A total of 14 eligible patients were enrolled in the study. Four patients received pre-surgery vaccines but were excluded from postsurgery vaccines due to the high-grade diagnosis of the resected tumor. No regimen-limiting toxicity was observed. All patients demonstrated a significant increase of anti-IMA950 CD8(+) T-cell response postvaccine in the peripheral blood, but no IMA950-reactive CD8(+) T cells were detected in the resected tumor. Mass cytometry analyses revealed that adding varlilumab promoted T helper type 1 effector memory CD4(+) and effector memory CD8(+ )T-cell differentiation in the PBMC but not in the tumor microenvironment.Conclusion: The combinational immunotherapy, including varlilumab, was well-tolerated and induced vaccine-reactive T-cell expansion in the peripheral blood but without a detectable response in the tumor. Further developments of strategies to overcome the blood-tumor barrier are warranted to improve the efficacy of immunotherapy for LGG patients.

2045 Background: Recurrence of GBM after initial treatment with surgery, radiation, and chemotherapy is nearly universal. Salvage therapies have limited efficacy with median overall survival (OS) of approximately 9 months and 6-month-progression-free survival (PFS-6) of 10-25% for both targeted and traditional therapies. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. Methods: The primary objective was to demonstrate the feasibility of implementing a personalized drug regimen for patients (pts) with surgically resectable recurrent GBM within 35 days of surgery. Secondary objectives included safety and efficacy. Eligible pts signed consent before surgery, and tumor tissue was analyzed using the CLIA-approved “UCSF500” next-generation sequencing panel with paired tumor/germline sequencing. A specialized genomic tumor board made individualized treatment recommendations incorporating sequencing results of the recurrent tumor and clinical history for each pt, using up to 4 FDA-approved drugs in combination (all drugs provided by study). Correlative studies will be reported separately. Results: 19 pts signed consent and 16 pts had surgery on trial, 1 with pathology showing treatment effect only. The remaining 15 pts were all genetically profiled and successfully started their individualized treatment within 35 days of surgery, meeting the primary feasibility endpoint. Conclusions: Implementation of an individualized treatment regimen was feasible in a timely fashion in surgically resectable recurrent GBM pts, with encouraging preliminary efficacy results. Further investigation is warranted, both to validate efficacy and to streamline this approach in larger pt populations. Clinical trial information: NCT03681028. [Table: see text]

Background. No studies have examined the fertility priorities of women undergoing treatment for their glioma. Glioma patients frequently undergo chemotherapy as part of their treatment; however, it is unknown whether patients truly are aware of its possible effects on their fertility. Our objective was to assess the fertility priorities of glioma patients and ascertain whether female glioma patients are being effectively counseled on the effects of chemotherapy on their fertility prior to beginning treatment. Methods. The sample was composed of female patients from the Neuro-oncology clinic of the University of California, San Francisco. Participants completed a cross-sectional survey between October 2010 and December 2013 exploring their attitudes toward fertility and their experience with fertility counseling prior to chemotherapy initiation. Results. Seventy-two women completed the survey. Analysis of the survey results showed that 30% of women receiving chemotherapy reported having a discussion regarding fertility preservation prior to beginning treatment. Of those who reported having this discussion, 80% were aware that chemotherapy could negatively affect their fertility. Many women reported that while fertility preservation was not important to them at the time of diagnosis, it was a priority for them at the time of survey completion. Although interest in having children tended to decrease after cancer treatment, the majority of respondents reported wanting a child after treatment. Conclusions. The data obtained in this study suggest a lack of understanding of reproductive priorities, which may be addressed with a more comprehensive fertility discussion prior to beginning treatment.

Preclinical activity of irinotecan has been seen in glioma models, but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic limitations. In preclinical testing, irinotecan liposome injection (nal-IRI) results in prolongation of drug exposure and higher tissue levels of drug due to slower metabolism and the effect of enhanced permeability and retention. The objective of the current study was to assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent high-grade glioma stratified based on UGT1A1 genotyping.

BACKGROUND: Patients diagnosed with a life threatening illness generally feel they have limited options in improving quality of life during this unexpected period in their lives.Learning to cope with such a debilitating disease can be difficult.. Being hopeful is often considered an important factor in personal adjustments but is plagued by illness-related uncertainty.We studied the relationship of Hope to disease status and symptom burden in primary brain tumor (PBT).METHODS: A cross-sectional sample of adult PBT patients completed the Hearth Hope Index (HHI).Data collection: patient completed demographic form, an investigator completed clinician checklist, the HHI, a 12-item assessment of hopefulness with 3 subscales (temporality and future, positive readiness/expectancy and interconnectedness).Descriptive statistics were used to describe the sample and HHI scores.Correlations between clinical characteristics, symptom burden and interference were explored.RESULTS: 71 patients (mean age 44.77(range 22 -78) participated in the study.Participants were primarily white (89.4%), male (56.3%) and married (74.6%) with a diagnoses of malignant glioma (glioblastoma, 38%) and no tumor recurrence(53.5%).Average HHI score was 41.09(range 13-48), subscales 13.69(range 4-16), with internal consistency of .0.70.Patients on active treatment had similar average hope scores but a wider range(range 13-48 vs. range 34-48) of scores than those in follow-up.Patients with recurrent tumors had lower total and subscale HHI scores.HHI Total score(r ¼ 20.31) and HHI Temporality(r ¼ 20.41) were negatively correlated with MDASI-BT Symptom Severity and HHI total(r ¼ 20.39), temporality(r ¼ 20.49) and interconnectedness (r ¼ 20.29) subscale scores were negatively correlated with MDASI-BT interference subscales.CONCLUSIONS: As expected, patients not on active treatment and without tumor recurrence reported higher levels of hope than their counterparts.Furthermore, the results indicate high symptom burden and interference is associated with lower hope scores.Future studies are needed to focus on this relationship to implement ways to improve one's coping skills in dealing with diagnoses and treatment changes.

BACKGROUND:Both the epidermal growth factor receptor and vascular endothelial growth factor pathways are frequently overexpressed in glioblastoma multiforme. This study combined bevacizumab, a vascular endothelial growth factor inhibitor, and erlotinib, an epidermal growth factor receptor inhibitor, with standard radiation and temozolomide (TMZ), with the goal of improving overall survival (OS).METHODS:Treatment consisted of fractionated radiotherapy to 60 Gy, with daily TMZ at 75 mg/m²/d and erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzyme-inducing antiepileptic drugs). Bevacizumab was given at 10 mg/kg every 2 weeks, starting ≥4 weeks after surgery. After radiotherapy, adjuvant TMZ was given at 200 mg/m²/d × 5d per 28-day cycle, with unchanged erlotinib and bevacizumab doses. Treatment continued until progression or for 12 months. Efficacy was compared against an institutional historical control. A sample of 55 patients was calculated to provide 85% power to detect a hazard ratio of 0.67 for OS.RESULTS:Fifty-nine patients were enrolled for efficacy analysis after a 15-patient safety lead-in. For the efficacy group, median age was 54 years; median KPS was 90. Gross total and subtotal resections were achieved in 33% and 53%, respectively. The most frequent related grade 3/4 adverse effects were lymphopenia, thrombocytopenia, neutropenia, diarrhea, weight loss, and fatigue. One patient died of disseminated aspergillosis. Median OS was 19.8 months (vs 18 mo for HC, P = .33) and median progression-free survival was 13.5 months (vs 8.6 mo for HC, P = .03).CONCLUSIONS:The combination of bevacizumab, erlotinib, TMZ, and radiotherapy appears to be well tolerated and improved progression-free survival but did not reach the primary endpoint of improved OS.

The purpose of this study is to identify the needs of brain tumor patients and their caregivers to provide improved health services to these populations. Two different questionnaires were designed for patients and caregivers. Both questionnaires contained questions pertaining to three realms: disease symptoms/treatment, health care provider, daily living/finances. The caregivers' questionnaires contained an additional domain on emotional needs. Each question was evaluated for the degree of importance and satisfaction. Exploratory analyses determined whether baseline characteristics affect responder importance or satisfaction. Also, areas of high agreement/disagreement in satisfaction between the participating patient-caregiver pairs were identified. Questions for which >50% of the patients and caregivers thought were "very important" but >30% were dissatisfied include: understanding the cause of brain tumors, dealing with patients' lower energy, identifying healthful foods and activities for patients, telephone access to health care providers, information on medical insurance coverage, and support from their employer. In the emotional realm, caregivers identified 9 out of 10 items as important but need further improvement. Areas of high disagreement in satisfaction between participating patient-caregiver pairs include: getting help with household chores (P value = 0.006) and finding time for personal needs (P value < 0.001). This study provides insights into areas to improve services for brain tumor patients and their caregivers. The caregivers' highest amount of burden is placed on their emotional needs, emphasizing the importance of providing appropriate medical and psychosocial support for caregivers to cope with emotional difficulties they face during the patients' treatment process.

The purpose of this study was to describe the quality of life (QOL) of low-grade glioma (LGG) patients at baseline prior to chemotherapy and through 12 cycles of temozolomide (TMZ) chemotherapy. Patients with histologically confirmed LGG with only prior surgery were given TMZ for 12 cycles. QOL assessments by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) were obtained at baseline prior to chemotherapy and at 2-month intervals while receiving TMZ. Patients with LGG at baseline prior to chemotherapy had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared to a normal population. Compared to patients with left hemisphere tumors, patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared to baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Patients with LGG on TMZ at baseline prior to chemotherapy reported QOL comparable to a normal population with the exception of social and emotional well-being, and those with right hemisphere tumors reported higher physical well-being scores compared to those with left hemisphere tumors. While remaining on therapy, LGG patients were able to maintain their QOL in all realms. LGG patients' QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working.

PurposeThis open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response.Patients and MethodsSixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials.ResultsMedian survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival.ConclusionPatients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.

2020 Background: ENZ, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathways to induce apoptosis, reduce proliferation, and suppress angiogenesis. The primary endpoint of this single-arm phase II trial was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, PK/PD, and patient-reported outcomes (PROs). A concurrent PGx project assessed the value of pretreatment molecular profiles as predictive of outcome. Magnetic resonance spectroscopy (MRS) was also evaluated during treatment for its value in predicting OS. Methods: Patients enrolled with newly diagnosed GBM/GS and KPS ≥60. Treatment started <5 weeks after diagnosis with RT 60 Gy given over 6 weeks and TMZ 75 mg/m 2 given daily during RT and then at 200 mg/m 2 from days 1–5 of a 28-day cycle. ENZ 250 mg/day was given daily during RT and adjuvantly. Planned treatment duration was 1 year. PGx parameters were: MGMT promoter methylation, mismatch repair status, PKC isoforms, pERK, pCREB, EGFR, PTEN, GSK3B, ser9, VEGF, and pS6. MRS was performed at baseline and at scheduled intervals. Changes in molecular signatures and imaging characteristics relative to survival were estimated using Kaplan-Meier and proportional hazards models. Analyses included phase I patients at ENZ 250 mg/day. Results: From September 2007 to November 2008, 60 phase II patients enrolled; 52 completed RT and eight are receiving RT. Of these, seven patients progressed immediately after RT and 17 progressed after one or more adjuvant cycles; five discontinued due to toxicity; four withdrew from trial. Treatment was well tolerated. The only toxicities seen in more than one-third of pateints were grade 1 fatigue, grade 1 nausea, and grade 1–2 lymphopenia. Grade 1 thrombocytopenia was seen in eight patients and grade 3 lymphopenia in five patients. OS, PFS, PROs, PGx, and imaging findings will be reported. Conclusions: The combination of ENZ plus TMZ during and following RT was well tolerated and may be an active regimen in GBM. This study represents the future of neuro-oncology clinical trial design by employing a novel multi-modal therapy while concurrently studying novel imaging and molecular techniques that may predict efficacy. [Table: see text]