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Purpose Several tumor types carry BRAF mutations and vascular endothelial growth factor pathway upregulation. Resistance mechanisms to BRAF inhibitors can include platelet-derived growth factor-β upregulation. Dabrafenib, a BRAF inhibitor, and pazopanib, a multikinase inhibitor that targets vascular endothelial growth factor and platelet-derived growth factor, have not been combined previously. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of the combination. Patients and Methods Patients with any advanced BRAF mutated malignancy with adequate organ function were eligible. Prior use of dabrafenib or pazopanib was not allowed. Dosages started at dabrafenib 50 mg twice a day and pazopanib 400 mg daily on dose level (DL) 1, with maximum dosages of 150 mg twice a day and 800 mg daily on DL5. Pharmacokinetics and BRAF V600E plasma clone were measured, and efficacy was evaluated by imaging and tumor markers every 8 weeks. Results Twenty-three patients with 11 different tumor histologies were enrolled in five DLs. Two dose-limiting toxicities were observed—a grade 3 bowel perforation on DL3 and grade 3 arthralgia on DL5. Common drug-related adverse events included nausea (52%), skin papules (43%), diarrhea (39%), hand-foot syndrome (30%), anemia (26%), rash (22%), vomiting (22%), hypophosphatemia (22%), and transaminitis (22%). Five patients (22%) experienced a partial response, including low-grade ovarian serous carcinoma, thyroid cancer, and glioblastoma multiforme, and two patients (appendiceal and thyroid cancer) had stable disease > 6 months. Pharmacokinetic measurements revealed pazopanib levels < 17.5 μg/mL in 80% of treated patients at steady state, particularly at DL5. BRAF V600E plasma copies correlated with response and progression. Conclusion Combination dabrafenib and pazopanib had no unexpected toxicities, and durable partial responses were observed at DL3 or greater. Dose escalation beyond DL5 may be considered as pazopanib levels were suboptimal as a result of drug interaction with dabrafenib.

Background Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. Patients and Methods In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR). Results Twenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively. Conclusion Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.

Most radiology and imaging nursing services are provided within hospital-based department services. However, improved access to portable ultrasound machines enables nurse-led ultrasound-guided procedures to be provided at the patient bedside and across other settings. The development of a nurse-led ultrasound-guided paracentesis service for oncology and other palliative care patients in regional New Zealand has improved patient choice and access to timely treatment. Between July 2009 and July 2017, approximately 500 ascites drains have been safely inserted by credentialed senior radiology nurses, with no complications. The service developed as a radiology hospital-based service, and in 2013, it was expanded to include an outreach service at the community-based local hospice.

Historically, cold injury, hypothermia, and frostbite have been severe problems for military units on the battlefield. Kenneth D. Orr and David C. Fainer captured these difficulties in their book, Cold Injuries in Korea During Winter of 1950-51, still cited in military medical readiness training. While not common in modern conflicts, the potential exists for large numbers of these casualties in war and during training.

Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.

6022 Background: BRAF mutations are present in ~44% of papillary thyroid carcinoma (PTC) and its role in development of PTC is well established. We hypothesized that dabrafenib (BRAF inhibitor) would have efficacy in BRAF mutated PTC and that combining it with trametinib (MEK inhibitor) would result in greater clinical efficacy than dabrafenib alone, through vertical inhibition of the RAF/MAP/ERK pathway and mitigation of potential mechanisms of resistance. Methods: Patients (pts) with BRAF mutated radioiodine refractory PTC who had evidence of disease progression within 13 months prior were randomized to Arm A (dabrafenib 150 mg PO BID) or Arm B (dabrafenib 150 mg PO BID + trametinib 2 mg PO qd). Cross-over to Arm B was allowed at time of progression. Responses were assessed by modified RECISTv1.1 every 2 months. Primary endpoint was objective response rate (ORR) (complete-, partial- and minor-response). With assumed true ORR of 15% vs 35%; and 90% power to identify the correct regimen as most promising, 26 pts were to be accrued in each Arm. Results: In this randomized phase 2 trial, 53 pts (median age 63 years, 38 females) were enrolled; 25% of pts had 1-3 prior therapy with multi-kinase inhibitors. Median follow up was 13 months. Preliminary efficacy results are outlined in Table. The treatment-related adverse events were similar to previously reported phase III clinical trial of these drugs in melanoma. Conclusions: Single agent dabrafenib, as well as combination of dabrafenib/trametinib are well tolerated therapies that result in similar high objective response rates with durable responses in pts with progressive BRAF-mutated PTC. BRAF-pathway targeted therapies provide novel treatment options. Clinical trial information: NCT01723202. [Table: see text]

Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile.Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle.Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response.Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723).

Background: Preclinical data demonstrates that activation of RAS/MEK/ERK pathway in basal-like breast cancer (BLBC) leads to resistance to chemotherapy. Inhibiting MEK pathway was highly effective in BLBC models with intact PTEN. Conversely activated PI3K/AKT pathway (loss of PTEN which occurs in ∼ 30% of TNBC) led to resistance to MEK inhibition. We proposed to test the hypothesis that single agent trametinib (T) will demonstrate efficacy in a subset of TNBC and that addition of AKTi, GSK2141795 (G) will overcome resistance to T. Methods: This is a single arm, multicenter study through the ETCTN. Eligible patients (pts) with advanced TNBC, measurable disease with 1-3 prior chemotherapies received mandatory research biopsy and entered Part I of the study with T alone (2 mg Q day-28 days). At the point of progression pts received a mandatory second biopsy and moved to PART II of study with 1.5 mg of T + 50 mg of G. Optional research biopsy was performed at the point of progression on the combination. Restaging scans were done every 2 cycles. Blood samples were collected at baseline, cycle 2 and at progression. Results: 33 pts with median age 55 (35-71) from six cancer centers were enrolled to Part I (T alone) and 17 pts entered part II (T +G). Most common toxicities for pts on T alone included Gr1: diarrhea, rash, transaminitis, Gr 2: fatigue; Gr 3: thromboembolism. Of 31 evaluable pts on T alone, two pts (1 still on study after 8 cycles) had a partial response (PR) and one pt has stable disease after 8 cycles and remains on study. Of the sixteen evaluable patients on part II (T+G) one patient has an unconfirmed PR (34% reduction on RECIST). Common toxicities for the combination include: Gr1: diarrhea, nausea, vomiting, myelosuppression, rash, hypertension, transaminitis, Gr2: Rash, fatigue, mucositis, diarrhea, Gr 3: diarrhea. Eleven patients died on study (10-progression, 1-adverse event). Blood and tissue samples are being analyzed for whole genome sequencing, IHC for PTEN, Quantitative targeted absolute proteomics (QTAP) for kinome assay and RPPA for PTEN, PI3KCA, AKT, ERK and MEK. This study is currently closed to accrual for interim analysis for efficacy on part II. Conclusion: Trametinib alone and in combination with AKTi, GSK2141795 has limited efficacy in TNBC. Proposed correlatives in serial biopsies may identify biomarkers in the few responders and help identify other novel targets. Citation Format: Bhuvaneswari Ramaswamy, Ewa Mrozek, Maryam Lustberg, Robert Wesolowski, Rachel Layman, Mahmoud Abdel-Rasoul, Cynthia Timmers, Robyn Patrick, Jennifer Sexton, Erin Macrae, Charles Shapiro, Thomas Budd, Lyndsay Harris, Claudine Isaacs, Roohi Ismail-Khan, Claire Dees, Andrew Poklepovic, Micheal Grever, Helen Chen, Miguel Villalona, William Carson. NCI 9455: Phase II study of trametinib followed by trametinib plus AKT inhibitor,GSK2141795 in patients with advanced triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-216.

146 Background: Tivantinib is a putative non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that has additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to castration resistance. Methods: 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival. PCWG2 guidelines were utilized for determining eligibility and progression. Results: Of the 80 pts enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluated. Median age was 67 yrs (range: 43 to 85). Baseline characteristics were balanced between arms for ECOG PS, Gleason score, PSA, LDH, hemoglobin, Alk Phos, prior treatment, bone and organ involvement. More African Americans and those with lymph node involvement were randomly assigned to placebo. Median follow up is 8.2 months (range: 1.4 to 27.6). To date 59 patients have progressed. Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.6 mo vs 3.8 mo, respectively; HR = 0.53, 95% CI: 0.32 to 0.89; p=0.015). Toxicity was mild overall. Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia were recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. 8 deaths (3 P and 5 tivantinib) have been recorded and were all considered unrelated to therapy. Conclusions: Tivantinib significantly improved PFS in men with asymptomatic or minimally symptomatic mCRPC. Given the favorable toxicity profile and evidence of anti-tumor activity, investigation of tivantinib with other agents may be a rational strategy. Clinical trial information: NCT01519414.

Aim: Reovirus is a naturally occurring virus that causes oncolysis in tumor cells with a Ras-activated pathway. It acts synergistically with taxanes. Since most pancreas cancer cells have downstream activated Ras we hypothesized that pts with MAP are susceptible to reovirus. Methods: We conducted an NCI-sponsored phase II study with a goal of 70 evaluable MAP pts randomized in a 1:1 allocation to paclitaxel [P (175 mg/m2)], carboplatin [C (AUC 5)] on day 1 with reovirus [R (3 x 1010 TCID50) iv] on days 1-5 {Arm A} vs P/C alone {Arm B} on day 1 of a 21-day cycle. The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rate (ORR), and overall survival (OS). Pts progressing on B were allowed to crossover to A. Eligible pts had no prior chemotherapy. Pre-treatment tissue was required for KRAS mutation status from DNA analysis. Analyses of immunomodulatory effects of therapy were performed. Results: Refer to Table 1 for key characteristics. Most common grade 3-4 toxicities include neutropenia (53%) and leucopenia (36%) with no overall difference between arms. In evaluable pts, ORR/SD was 22%/59% (A) and 21%/47% (B). To date, 81% have progressed, and median follow-up of 3.75 mo in event-free pts. PFS was similar in both arms (A: median 4.63 vs B: 5.1 mos; HR = 1.07, p = 0.81). The results held after sensitivity analyses and adjusting for factors such as KRAS. In 60 patients with KRAS analysis, a trend toward improved overall PFS in KRAS WT (6.0 mo) vs MT (4.3 mo); p = 0.20. In the KRAS MT group, an early limited differential in PFS between arm A (4.63 mo) vs B (4.34 mo); p = 0.73. 16 pts crossed over from B to A with 1 PR, 6 SD, 7 PD and 2 NA. Characteristic Arm A Arm B p-value Total N = 73 36 37 Age (Median, yrs) 61.5 66 0.055 ECOG PS (0/1), N 20/16 17/20 0.49 Baseline Ca 19-9 of > 59x ULN, % 53% 75% 0.14 KRAS Status ( MT), % 70% 77% 0.99 Pancreas Tumor Location, % Head Body Tail NS 22 36 22 22 27 38 19 14 Number of Metastatic Sites, % 1 2 >2 19 30 51 22 14 66 0.51 Conclusions: Reovirus can be administered safely in combination with P/C in pts with MAP. Both arms performed better than historical control, but R did not seem to improve outcome when added to P/C in MAP. This is the first report of P/C in MAP, which proved to have higher activity than anticipated, suggesting that similar to other disease settings, a relatively inexpensive taxane is an acceptable choice in MAP. A pharmaco-economic analysis is underway. Disclosure: T. Bekaii-Saab: Research Funding: Oncolytics Biotech; M.A. Villalona-Calero: Research Grant : Oncolytics Biotech. All other authors have declared no conflicts of interest.

7063 Background: Effective treatments (tx) for classical (c) HCL pts refractory to or ineligible for nucleoside analogs (NA) are limited, and there is no accepted standard for either tx-naive or re...

TPS2628 Background: BRAF inhibitor therapy is associated with an impressive albeit short-lived response rate in the treatment of malignant melanoma. Mechanisms of resistance include upregulation of...