Jaeckle, Kurt A.

Abstract BACKGROUND Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis. METHODS Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The kappa coefficient (K) was used to evaluate inter-observer pairwise agreement. Statistical analyses were performed using SAS V9.4 software (Cary, NC). The sponsor of the study was the University Hospital Zurich (2018-00192). RESULTS Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among leptomeningeal metastases-related items at baseline, the best median concordance was noted for hydrocephalus (K=0.63), and the worst median for spinal linear enhancing disease (K=0.46). The median concordance for overall response was moderate (K=0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was minimal (K=0.29). Significant differences were observed when considering the specialty of the raters. Only 394 of 700 ratings (56%) were fully completed. Among 394 fully completed ratings, perfect concordance was noted in 293 ratings (74%) when comparing the overall response according to the guidelines provided in the scorecard and the overall response provided by the raters. The main discordances were noted for partial response according to the rater versus stable disease according to the guidelines (n=44), followed by progression according to the raters versus stable disease according to the guidelines (n=23). CONCLUSION Electronic case report forms with "blocking solutions" are probably required to enforce completeness and quality of scoring. These results confirm the necessity of central review and the need for training of MRI assessment in clinical trials.

TPS350 Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) are found in approximately 20-30% of patients with intrahepatic cholangiocarcinoma (CCA), and less commonly in glioma, chondrosarcoma, and other gastrointestinal malignancies. Despite documented clinical activity of mIDH1 inhibition in solid tumors, there are no approved targeted therapies for this patient population. LY3410738 is a potent, selective, and covalent inhibitor of mIDH1 R132. LY3410738 is differentiated from prior mIDH1 inhibitors by 1) its unique covalent binding mode, 2) its increased potency, and 3) its unique binding site outside of the dimer interface, which enables activity in the setting of known common second-site IDH1 mutations. Methods: This is an open-label, multicenter, global phase 1 study with oral LY3410738 currently enrolling patients with advanced CCA and other solid tumor types (NCT04521686). A dose escalation cohort will be followed with 4 exploratory expansion cohorts. The primary objective for dose escalation is determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary objective for dose expansion is to assess the preliminary anti-tumor activity by ORR of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine. Secondary objectives include evaluating safety and tolerability, pharmacokinetics, pharmacodynamics, progression free survival, and overall survival. Key inclusion criteria include any solid tumor with the presence of mIDH1 R132, ECOG performance status ≤1, and adequate organ function. Any prior treatment including an IDH1 inhibitor is allowed in the dose escalation cohort. Exclusion criteria include presence of active central nervous system metastases, leptomeningeal disease, and active or uncontrolled infection. CCA patients must not have had locoregional therapy within 4 weeks prior to the initial study dose, history of hepatic encephalopathy or refractory ascites, ongoing cholangitis, or mixed hepatocellular-CCA histology. Dose escalation will follow a 3+3 design and will allow patient back-fill to dose levels previously cleared for safety. Each cycle will be 28 days (4 weeks). Once the RP2D is determined, LY3410738 will be evaluated as monotherapy in expansion cohorts 1-3, and in combination with cisplatin plus gemcitabine in expansion cohort 4. Cohort 1 will enroll CCA patients with measurable disease who have received prior chemotherapy. Cohort 2 will enroll patients with advanced solid tumors except CCA who have measurable disease and received standard therapies. Cohort 3 will enroll patients with advanced solid tumors who have non-measurable disease and received standard therapies. Cohort 4 will enroll CCA patients with measurable disease who are treatment naïve for advanced disease. Clinical trial information: NCT04521686.

Abstract BACKGROUND The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design. METHODS Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm. RESULTS 36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms. CONCLUSIONS TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.

AbstractBackgroundThere are few treatment options for patients with leptomeningeal metastases (LM).MethodsWe report a case series of patients with breast cancer and LM treated with intra‐CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4‐5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment.ResultsThirty‐one women [median age, 58 (37‐81); median KPS 60 (40‐100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3‐71); median duration of treatment, 11 weeks (1‐176); and median OS, 6.9 months (range, 0.9‐48.8). Patients remaining progression‐free during 4‐6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8‐48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4‐34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts).ConclusionsIntra‐CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS.

2019 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. We previously demonstrated significant synergy of the mTOR inhibitor sirolimus with RT in glioma xenografts. Methods: The standard cohorts of 3 design was applied with dose escalation of weekly IV CCI-779 in combination with standard TMZ/RT. CCI-779 was given during both RT (60 Gy)/TMZ (75 mg/m2 daily) and adjuvant TMZ (200 mg/m2 daily x 5 every 28 days). Results: A total of 17 patients were enrolled. CCI-779 therapy during RT/TMZ was well tolerated at dose level 0 (25 mg CCI-779, n = 3) and dose level 1 (50 mg CCI-779, n = 6) with 1 of 9 patients experiencing a DLT (Gr 3 fatigue). Dose level 2 (75 mg CCI-779) exceeded the maximally tolerated dose with two of six patients with DLT (<75% CCI-779 delivered; Gr 4 dyspnea). Despite reasonable tolerance during RT/TMZ, the overall regimen was associated with a high rate of infection associated with lymphopenia. After a patient died from PCP on cycle 2 of adjuvant TMZ/CCI-779, antibiotic prophylaxis was mandated. Two other patients died of gram-negative sepsis despite prophylaxis: one after their first dose of CCI-779 and one during cycle 4 of adjuvant therapy. In contrast to our 18% grade 5 infection rate, only 4% grade 3 (no grade 4/5) infections were observed in 26 other CTEP-sponsored clinical trials involving 1,006 patients treated with CCI-779. Results from translational studies evaluating the effects of treatment on immune function will be presented. Further infections were avoided on this trial after CCI-779 therapy was limited to RT/TMZ. Conclusions: Although CCI-779 in combination with RT/TMZ was well-tolerated, adjuvant therapy with TMZ/CCI-779 was associated with an increased risk of opportunistic infections. [Table: see text]

Abstract Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (&gt;18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. Results Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. Conclusions TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.

12007 Background: Up to 96% of patients with high grade glioma (HGG) report moderate to severe fatigue. Armodafinil, the R-enantiomer of modafinil, is a psychostimulant with low potential for abuse that has shown potential for improving severe fatigue in HGG patients. Methods: In this phase III double blinded placebo-controlled study, adults with HGG and moderate to severe fatigue, > 4 weeks after completing radiotherapy, were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo for a total of 8 weeks. The primary outcome was efficacy in treating severe fatigue. Secondary outcomes included evaluation of tolerability, neurocognitive function, and quality of life. Patients were evaluated at baseline, 4 and 8 weeks. Results: A total of 328 patients were enrolled between 6/3/13-3/1/19. There were 103 (150 mg arm), 97 (250 mg arm) and 97 (placebo arm) evaluable patients with primary endpoint data available. The median age was 60 years (20-85) with a median Brief Fatigue Inventory (BFI) worst fatigue score of 8 (6-10). 60.3% were male, 80.5% received concomitant chemotherapy, and 39.7% were on corticosteroids. The global fatigue score at end of weeks 4 and 8 were lower than at baseline (p<0.0001) and in the 250 mg arm than placebo (p=0.0356) and was higher for corticosteroid users than non-users (p=0.0002). There was no statistically significant difference for clinically meaningful improvement in BFI usual fatigue score from baseline to end of week 8 between the three arms (p=0.9601). Patients reported an improvement in concentration at week 4 from baseline on the 150 mg arm(P=0.0311). There was no statistically significant difference on neurocognitive tests from baseline to end of week 4 (p>0.05) or week 8 (p>0.05) between arms. More patients reported insomnia on the 250 mg arm (p=0.0083). Conclusions: There is no meaningful benefit of the use of armodafinil to reduce moderate to severe fatigue in patients with HGG. In certain cases there may be benefit of armodafinil 150 mg to aid concentration without the risk of insomnia.Support: UG1CA189823;U10CA180868 (NRG). Clinical trial information: NCT01781468 .

8583 Background: Patient QOL assessment requires balancing the detail provided by multi-item assessments with the reduced burden of single-item assessments. We investigated the psychometric properties of single-item LASA assessments used in 3 North Central Cancer Treatment Group (NCCTG) phase II trials for patients with newly diagnosed high-grade gliomas. Methods: Measures included QOL LASAs (overall, physical, emotional, spiritual, intellectual), Symptom Distress Scale (SDS), Profile of Mood States (POMS), and Functional Assessment for Cancer Therapy (FACT; overall, physical, emotional). Association of LASA measures with SDS, POMS, and FACT domains and with ECOG performance score (PS) and MMSE was assessed with Spearman’s correlation. Repeated measures ANOVA models compared the change over time of LASAs and SDS, POMS, and FACT. Cox regression modeled the association of baseline QOL and survival. Results: 205 patients completed the QOL assessments across 3 time points. LASA mean scores ranged from 60–78; SDS, POMS, and FACT ranged from 68–81. No significant changes across time for overall and emotional scores were observed. FACT physical decreased over time (p<0.001) as did LASA physical (p=0.08). LASA scales were strongly associated with corresponding scales on SDS, POMS, and FACT (0.44<rho<0.65; p<0.001). LASA was negatively associated with PS and positively with MMSE. Baseline scores for overall FACT (p=0.005) and LASA physical (p=0.015) were associated with better survival. Conclusions: The single-item LASA assessments have comparable psychometric properties as longer assessments for the same constructs. Correlations with PS and MMSE were as expected (convergent/concurrent validity). The discriminant validity and prognostic ability of LASA items were similar to the multi-item instruments. Collectively, the data suggest that the single item LASA scales are valid for assessing QOL in patients with newly diagnosed high grade gliomas and are an appropriate alternative when a shorter instrument is warranted. No significant financial relationships to disclose.

LBA2010 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.