Search

BackgroundThe landmark study of durvalumab as consolidation therapy in NSCLC patients (PACIFIC trial) demonstrated significantly longer progression-free survival (PFS) in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with durvalumab (immunotherapy, IO) therapy after chemoradiotherapy (CRT). In clinical practice in the USA, durvalumab continues to be used in patients across all levels of programmed cell death ligand-1 (PD-L1) expression. While immune therapies have shown promise in several cancers, some patients either do not respond to the therapy or have cancer recurrence after an initial response. It is not clear so far who will benefit of this therapy or what the mechanisms behind treatment failure are.MethodsA total of 133 patients with unresectable stage III NSCLC who underwent durvalumab after CRT or CRT alone were included. Patients treated with durvalumab IO after CRT were randomly split into training (D1=59) and test (D2=59) sets and the remaining 15 patients treated with CRT alone were grouped in D3. Radiomic textural patterns from within and around the target nodules were extracted. A radiomic risk score (RRS) was built and was used to predict PFS and overall survival (OS). Patients were divided into high-risk and low-risk groups based on median RRS.ResultsRRS was found to be significantly associated with PFS in D1 (HR=2.67, 95% CI 1.85 to 4.13, pConclusionsTumor radiomics of pretreatment CT images from patients with stage III unresectable NSCLC were prognostic of PFS and OS to CRT followed by durvalumab IO and CRT alone.

PURPOSE State and national cancer registries do not systematically include Veteran data, which hinders analysis of the diagnosis patterns, treatment trajectories, and clinical outcomes of Veterans compared with non-Veteran populations. This study used data matching approaches to compare cases included in the Oncology Domain of the Veterans Affairs (VA) Corporate Data Warehouse and the Ohio Cancer Incidence Surveillance System, using brain tumors as an exemplar. METHODS We used direct data matching, on the basis of protected health information (PHI) common to both databases, to compare primary brain tumors from Veterans and non-Veterans diagnosed from 2000 to 2016. Working with this matched data set, we used six data elements that did not contain PHI, to assess the feasibility of using deterministic data matching to compare Veterans and non-Veterans. RESULTS Between 2000 and 2016, 223 Veterans from Ohio had a primary brain tumor; of those, 55 (25%) were not included in Ohio Cancer Incidence Surveillance System. Direct data matching showed that Veterans experienced a greater proportion of glioblastomas (41%) compared with non-Veterans (21%). Sex did not account for this difference. Deterministic data matching within the matched data set found that 75% (126 of 168) of Veterans had exact matches for at least five of six non-PHI variables common to both databases. CONCLUSION This study indicated that direct and deterministic data matching approaches to compare brain tumors in Veterans and in non-Veterans is feasible. This approach has the potential to promote comparisons of the distribution of tumors, the impact of chemical and environmental exposures, treatment trajectories, and clinical outcomes among Veteran and non-Veteran populations with brain tumors as well as other cancers and rare diseases.

Background Metabolic syndrome is identified as a risk factor for the development of several systemic cancers, but its frequency among patients with glioblastoma and its association with clinical outcomes have yet to be determined. The aim of this study was to investigate metabolic syndrome as a risk factor for and affecting survival in glioblastoma patients. Methods A retrospective cohort study, consisting of patients with diagnoses at a single institution between 2007 and 2013, was conducted. Clinical records were reviewed, and clinical and laboratory data pertaining to 5 metabolic criteria were extrapolated. Overall survival was determined by time from initial surgical diagnosis to date of death or last follow-up. Results The frequency of metabolic syndrome among patients diagnosed with glioblastoma was slightly greater than the frequency of metabolic syndrome among the general population. Within a subset of patients (n = 91) receiving the full schedule of concurrent radiation and temozolomide and adjuvant temozolomide, median overall survival was significantly shorter for patients with metabolic syndrome compared with those without. In addition, the presence of all 5 elements of the metabolic syndrome resulted in significantly decreased median survival in these patients. Conclusions We identified the metabolic syndrome at a slightly higher frequency in patients with diagnosed glioblastoma compared with the general population. In addition, metabolic syndrome with each of its individual components is associated with an overall worse prognosis in patients receiving the standard schedule of radiation and temozolomide after adjustment for age.

e21148Background: Utilization of immunotherapy in the veteran population with lung cancer is not well described. The purpose of this study was to evaluate the use of nivolumab (nivo) versus chemoth...

Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.

Background Brain metastasis is common in patients with malignant mela-noma and represents a significant cause of morbidity and mortality. Nearly 37% of patients with malignant mela-noma eventually develop brain metastasis, and autopsy reports show that 75% of those who died of this disease developed brain metastasis. Methods We review the level I and level II evidence that guides indications for treatment with surgery, stereotactic radiosurgery, chemotherapy, and immunotherapy for patients with mela-noma brain metastasis. Results Level I evidence supports the role of whole brain radiotherapy, microsurgery, and radiosurgery alone or in combination for the treatment of patients with mela-noma brain metastasis. Chemotherapy has been ineffective. Ongoing studies continue to assess the effects of immunotherapy and agents in development. Conclusions Brain metastasis is a common and formidable challenge in patients with malignant melanoma. Although there have been no randomized controlled trials exclusively in patients with mela-noma brain metastasis, care can be guided by the application of level I evidence for the treatment of brain metastasis in general and phase II studies focusing specifically on mela-noma brain metastasis. Promising new agents and approaches are needed and will hopefully be identified in the near future.

Purpose Cytotoxic and anti-angiogenic drugs are efficacious in malignancies. This trial was undertaken to evaluate the toxicity of a novel regimen combining docetaxel and lenalidomide. Patients and methods Patients with advanced solid tumors were eligible. Docetaxel was administered on day 1, and lenalidomide was given on days 1–14 of each 21-day cycle. Since significant myelosuppression occurred, pegfilgrastim was added on day 2. Dose limiting toxicity (DLT) was defined as ≥grade 3 non-hematologic toxicity, grade 4 neutropenia with fever, or grade 4 anemia or thrombocytopenia. Results Thirty-three patients were enrolled. DLTs included neutropenia, nausea/vomiting, and dyspnea. Of the evaluable patients, 69% had stable disease, and 3% had partial response. Conclusions This regimen was well tolerated and provided stable disease in the majority of advanced cancer patients. The recommended phase II dosing is docetaxel 75 mg/m2 on day 1, lenalidomide 25 mg on days 1–14, and pegfilgrastim 6 mg on day 2, given every 3 weeks.

Purpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m2/week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Dose-limiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m2/week.

Glioblastoma (GBM) is the most common and the most malignant primary brain tumor in adults, accounting for ~12–15% of all intracranial neoplasms. Despite advances in surgical, medical and radiation therapies, the mortality of GBM remains high, with a median survival ranging between 40 and 70 weeks. Similar to other primary brain tumors, the extracranial metastasis of GBM is extremely rare, occurring in

To determine the safety, the maximal tolerated dose, and to assess for any clinical activity of pomalidomide given to patients with advanced solid tumors.Patients with incurable solid tumors were enrolled. Two different dosing schedules were explored. In Cohort A patients were given pomalidomide once daily for 21 days followed by a 7 day rest. For Cohort B additional patients were recruited to receive pomalidomide given once daily for 28 consecutive days. Dose-limiting toxicity was defined as ≥grade 3 non-hematological toxicity that occurs during cycle 1 and that does not resolve to ≤grade 1 by day 35. Subjects must have received optimal symptomatic treatment for ≥grade 3 nausea, vomiting, or diarrhea to be considered a DLT. Grade 4 transaminitis was considered to be a DLT while grade 3 transaminitis must be present7 days to be a DLT. Grade 3 febrile neutropenia was considered a DLT. Grade 4 neutropenia, without a fever, was a DLT if the neutropenia did not improve to ≤grade 1 by day 35 of cycle one. Platelet count ≤25,000/mm(3) must improve to ≥75,000/mm(3) by day 35 of cycle one in order not to be considered a DLT. If a patient did not complete one cycle of therapy, for reasons other than a DLT, a replacement subject was added to the same cohort level.A total of 40 patients were enrolled. In Cohort A, three patients received pomalidomide at 5 mg daily without any significant toxicity. Two patients in the 10 mg cohort experienced dose-limiting toxicities of two episodes of grade 3 dyspnea and one grade 4 neutropenia. Six patients were then enrolled at the 7 mg daily of pomalidomide, and no dose-limiting events were observed. In Cohort B, 29 patients were enrolled and the maximal tolerated dose was 4 mg once daily. Stable disease in a variety of tumors was observed.Pomalidomide was well tolerated and the recommended phase II dosing schedules are 7 mg daily given for 21 days followed by a 7-day rest or pomalidomide 4 mg given on an uninterrupted daily schedule.

e14607 Background: Carcinoembryonic antigen (CEA) is a commonly used tumor marker in colorectal cancer (CRC) but has poor sensitivity (59%) and specificity (84%). Vimentin exon-1 sequences are hype...

Background. Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. Methods. Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. Results. Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8–6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6–3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. Conclusion. Single-agent dasatinib does not have clinical activity in metastatic PDAC.

BACKGROUND: New therapeutic approaches are urgently needed for recurrent GBM (rGBM). Recent studies suggest that GBM oncogenesis and recurrence are regulated by glioma initiating cells (GIC), a minority population of quiescent cells driven by embryonic signaling pathways and resistant to radiation and chemotherapy. Our hypothesis was that interrupting the sonic hedgehog signaling pathway (SHh), an integral mediator of GIC proliferation, would slow tumor progression and improve six month progression free survival (PFS6) in correlation with decreased GSC proliferation and self-renewal. METHODS: A two armed, randomized phase 0/II study of Vismodegib, an inhibitor of SMO was performed in 40 patients undergoing resection for rGBM. Arm I was randomized to receive Vismodegib for 7 days pre-operatively; Arm II was not treated with drug pre-operatively. All patients were treated with Vismodegib alone post-operatively until progression or death. Our primary objective was to estimate six month progression-free survival (PFS6), with secondary endpoints of median overall survival (mOS), response and toxicity. Secondary objectives included determination of: intra-tumoral PK and PD; inhibition of SHh signaling by RT-PCR and immunohistochemistry; and inhibition of GIC proliferation and self-renewal by neurospheres proliferation and limited dilution assays. RESULTS: PK/PD data and tumor specimens obtained from 39/40 patients demonstrated plasma and tissue levels for patients in Arm I (treated pre-operatively) were within therapeutic range. SHh signaling intermediates (Gli-1, Gli-2, PTCH-1b) as determined by RT-PCR and IHC were significantly lower in Arm I vs. Arm II (p < 0.0002). Finally, proliferating CD133 + neurospheres in serum free-media were derived from 17 of the 39 cultures assessed. Array CGH was consistent with GIC (rather than NSC) as the cells of origin, and the proportion of tumor-derived CD133+ neurospheres undergoing proliferation and self-renewal was decreased in Arms I vs. II (p

2026 Background: The prognosis for GBM, which appears to be driven by glioma initiating cells (GIC), remains poor. Our hypothesis was that interrupting sonic hedgehog signaling (SHh) would inhibit ...

TPS1616 Background: The administration of radiation therapy (RT) and concomitant and adjuvant temozolomide (TMZ) for the treatment of newly-diagnosed glioblastoma (GBM) is associated with modestly prolonged survival. However, the benefit of concurrent therapy is restricted to a subgroup of patients whose tumor exhibits methylation of the promoter for methylguanine-DNA-methyltransferase (MGMT). Promoter methylation silences the expression of DNA alkyltransferase (AGT), the product of the MGMT gene which functions to repair alkylated DNA. Unfortunately, the majority of GBMs have non-methylated MGMT promoters and do not appear to benefit from adding TMZ to radiotherapy. Two potential strategies for targeting MGMT-induced chemoprotection in gliomas include depletion of tumor MGMT, and dose escalation of TMZ accomplished by minimizing TMZ-induced bone marrow toxicity. In this study, we propose to combine the irreversible MGMT inhibitor O6-benzylguanine (BG) with infusion of autologous hematopoetic stem cells (HSCs) transduced with lentiviral P140K-MGMT, an MGMT mutant which is highly resistant to inactivation by BG, with the intent to reduce or prevent the myelosuppressive effects of TMZ. The primary objective is to assess the safety and feasibility of combining these two strategies in patients with newly-diagnosed GBM. Methods: This is a three cohort, Phase I study for patients with newly resected supratentorial GBM. There will be at least four evaluable patients per cohort. Cohort 1 will receive standard RT and concomitant TMZ prior to infusion of autologous lentiviral P140K-MGMT transduced HSCs, followed by adjuvant TMZ. Cohort 2 will receive an induction dose of TMZ+BG followed by infusion of autologous LV-P140K-MGMT HSCs prior to concomitant RT +TMZ and adjuvant TMZ. Cohort 3 will include intra-patient dose escalation of TMZ in patients who exhibit detectable levels of P140K-MGMT marked cells in vivo, using the design (i.e. cohort 1 or 2) proven to be safest and most effective. The study is open and has accrued the first patient.

Objective: Report the frequency of metabolic syndrome (MS) in newly-diagnosed glioblastoma (NGBM) patients and impact of MS on patient survival. Background The MS is a well-established risk factor for atherosclerotic cardiovascular and cerebrovascular disease. It has been identified as a risk factor for some systemic cancers and as a predictor of worse clinical outcome in systemic cancer. There is limited evidence for obesity and hyperglycemia as predictors of poor outcome in malignant glioma patients (Chambless 2011). The frequency of MS and its impact on survival of NGBM patients has not been determined. Design/Methods: We retrospectively reviewed records of all patients (N = 114) with NGBM at University Hospitals Case Medical Center from 2007-2011. Criteria for MS included > 3 of elevated fasting glucose, hypertension, elevated triglycerides, reduced high density lipoprotein C (or history of these or history of treatment for them), and obesity. The criteria had to be present prior to diagnosis of GBM. Results: MS was identified in 44/114 patients (39%). Mean patient age was 65 years (67 with MS, 64 without MS). The majority received radiation, typically with temozolomide. Median survival by MS status was 7 months for those with MS and 12 months for those without MS (p = 0.0456). After adjustment for other prognostic factors, median survival was shorter for those with MS (8 months) versus those without (10 months), but this did not reach statistical significance (p > 0.05). Conclusions: MS was identified in 39% of NGBM. The presence of MS was associated with an unadjusted lower median survival compared to patients without MS. After adjustment for independent prognostic factors, this survival difference was not significant. Because of potential limitations due to the retrospective design of this study, we will perform a prospective study to determine the impact of MS on survival of NGBM patients. Disclosure: Dr. Rogers has received personal compensation for activities with Sigma Tau Pharmaceuticals as a speaker. Dr. Vengoechea has nothing to disclose. Dr. Ostrom has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Davitkov has nothing to disclose. Dr. Strodtbeck has nothing to disclose. Dr. Selman has nothing to disclose. Dr. Gerson has nothing to disclose. Dr. Nock has nothing to disclose. Dr. Machtay has nothing to disclose. Dr. Lo has nothing to disclose. Dr. Sloan has received personal compensation for activities with RealBio and Nanotech Solutions. Dr. Sloan has received research support from the NIH, Lentigen, RealBio, Nantech, Genentech, the Cristal Chair, and the Kimble Foundation. Dr. Barnholtz-Sloan has nothing to disclose.

e13077 Background: Pomalidomide is an IMiD analogue of thalidomide and on an equimolar basis in vitro, displays a greater stimulation of apoptosis, inhibition of COX-2 production, and inhibition of...

13533 Background: Sunitinib malate (S) is an oral multi-targeted tyrosine kinase inhibitor (TKIs) with affinity for VEGFRs, PDGFRs, KIT, RET, and Flt3. These targets are significant in several mali...

15076 Background: Pre-clinical and clinical data suggest epidermal growth factor receptor (EGFR)-inhibition may augment the activity of FOLFOX as treatment of MCRC. The severity of rash induced by ...

3585 Background: CC-4047 is an IMiD™ compound with immunomodulatory properties and on an equimolar basis in vitro, displays equivalent anti-angiogenic properties; however, CC-4047 gives a greater s...

3530 Background: Sunitinib is an oral multi-targeted inhibitor of VEGFR-2 and related receptors. Bevacizumab is an antibody that binds to VEGF. The safety, tolerability, and clinical activity of su...