Reid, Joel M.

10017 Background: In preclinical models, temozolomide (TMZ) and vincristine (VCR) are synergistic with irinotecan (IRN). We sought to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally administered IRN given on two different schedules together with TMZ and VCR in children with refractory solid tumors, using cefixime to reduce IRN-associated diarrhea. Methods: Schedule A: Oral IRN daily for 5 days for 2 weeks (dx5x2), with VCR 1.5 mg/m2 on days 1 and 8 and TMZ 100 mg/m2 on days 1 - 5. Schedule B: Oral IRN daily for 5 days for 1 week (dx5x1) with VCR 1.5 mg/m2 on day 1 and TMZ 100 - 150 mg/m2 on days 1 - 5. Courses were repeated every 3 weeks. A standard cohorts of 3 + 3 design was used. Results: On Schedule A, 18 evaluable patients (median age 15 yrs, range 3 - 21) received 55 courses. At IRN 50 mg/m2/day, 4/12 pts had DLT (hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia). The oral IRN MTD on this dx5x2 schedule was 35 mg/m2/d (1/6 pts with DLT of hypoalbuminemia). On Schedule B, 18 evaluable patients (median age 9 yrs, range 3–21) received 71 courses of oral IRN 70 - 90 mg/m2/d x 5 with TMZ 100 - 150 mg/m2/d x 5. At oral IRN 90 mg/m2/d with TMZ 150 mg/m2/d, 0/6 pts had DLT, and no Grade 4 toxicities were seen. No further doses were explored. First-course and cumulative toxicity appeared worse with Schedule A, including 3 patients with responding or stable tumors who withdrew due to fatigue, nausea, and weight loss. UGT1A1*28genotype did not correlate with DLT. At the oral IRN MTD of 90 mg/m2/d, the median SN-38 AUCinf was 72 ng/ml*h. One patient with osteosarcoma had a confirmed partial response. Unconfirmed complete and partial responses were seen in 2 Ewing sarcoma patients. Eight additional patients received > 6 courses, including 2 each with neuroblastoma and medulloblastoma. Conclusions: The dx5x1 schedule of VOIT was well tolerated, with SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in sarcoma patients. No significant financial relationships to disclose.

TPS10560 Background: In children, fusions of the NTRK1/2/3 genes (TRK fusions) occur in soft tissue sarcomas, including infantile fibrosarcoma (IFS), congenital mesoblastic nephroma, high- and low-grade gliomas, secretory breast carcinoma, and papillary thyroid cancer. Rarely, TRK fusions also occur in Ph-like acute lymphoblastic leukemia and acute myeloid leukemia. Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. In children, larotrectinib demonstrated a 94% overall response rate (ORR) with a 12-month progression free survival rate of 75% (1). Methods: Patients <30 years with any newly diagnosed unresectable solid tumor or relapsed/refractory acute leukemia with TRK fusions are eligible. TRK fusions must be locally identified in a CLIA/CAP laboratory and are confirmed centrally using a targeted RNA sequencing panel. Patients with high-grade gliomas are excluded. Patients receive larotrectinib 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles. Patients with solid tumors who achieve CR will discontinue larotrectinib at the completion of at least 12 total cycles of therapy and 6 cycles after achieving CR. Those whose tumors become surgically resectable may undergo on study resection and discontinue therapy if an R0/R1 (IFS) or R0 (other tumors) resection is obtained. All other patients will receive 26 cycles in the absence of unacceptable toxicity or progressive disease. The primary endpoint is the ORR to larotrectinib according to RECIST 1.1 in children with IFS. The study uses a Simon 2-stage minimax design, and the regimen will be considered of sufficient interest if 16 of 21 (76%) patients with IFS demonstrate response. Patients with other solid tumors and leukemias will be analyzed in separate cohorts as secondary objectives. Correlative studies include serial sampling of circulating tumor DNA and neurocognitive assessments. This is the first Children’s Oncology Group study to assign frontline therapy based on the presence of a molecular marker independent of histology, and the first clinical trial to evaluate larotrectinib for the treatment of leukemia. Enrollment began in October 2019 (NCT03834961). 1. Tilburg CMv, DuBois SG, Albert CM, et al: Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients. Journal of Clinical Oncology 37:10010-10010, 2019 Clinical trial information: NCT03834961.

e22020 Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m2 NP /50 mg/m2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m2 NP/40 mg/m2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m2 NP/ 60 mg/m2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.

10526 Background: Pro-angiogenic factors may represent therapeutic targets in sarcoma. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and chemotherapy. The purpose of this study was to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetic (PK) and pharmacodynamics (PD) effects of PAZIT in patients with advanced sarcoma. Methods: Patients 6-30 years of age with relapsed/refractory sarcomas were eligible. In the initial dose escalation plan (A), patients received pazopanib PO (225-450 mg/m2/dose) on Days 1-21 of 21-day cycles. Pazopanib was combined with fixed doses of irinotecan (IV 50 or PO 90 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Due to DLTs, an amendment was made to the dose escalation plan (B) and patients received fixed doses of pazopanib PO (225 mg/m2/dose) on Days 1-21 of 21-day cycles and reduced irinotecan doses (IV 25-37.5 or PO 45-67.5 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Oral cephalosporin diarrhea prophylaxis was required. Dose escalation followed a 3+3 design. Correlative studies included PK (pazopanib, irinotecan) and PD (angiogenic factors, ctDNA) effects. Results: Sixteen patients were treated (median age 16 years, range 7-21). The dose levels in the table were evaluated. First cycle DLTs occurred at all dose levels (Table) and included diarrhea, pancreatitis, colitis, neutropenia, hypertension, deep vein thrombosis, and ALT increase. Due to excessive toxicity, an MTD could not be established. One patient with osteosarcoma had a partial response. Four patients had prolonged stable disease > 4 cycles, including 2 patients with Ewing sarcoma (5 and 6 cycles), rhabdomyosarcoma (9 cycles), and desmoplastic small round cell tumor (6 cycles). Mean±SD plasma exposures to pazopanib, irinotecan, and SN-38 in patients treated on dose level 1B (n = 4) on Day 4 were 601±83, 1.4±0.2 and 0.1±0.04 ug/mL*hr, respectively. Analyses of correlative studies are ongoing. Conclusions: Combination PAZIT therapy is not tolerable as evaluated at these doses/schedules. This study provides important toxicity data to inform future clinical trials using combination anti-angiogenic strategies in sarcoma. Clinical trial information: NCT03139331. [Table: see text]

e18097 Background: AB160 is a 160 nm nano-immunoconjugate consisting of nab-paclitaxel (NP) nanoparticles non-covalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of vascular-endothelial growth factor (VEGF). Both taxanes (GOG-0129C, GOG-0126R, GOG-0127V) and BEV (GOG-0229E, AURELIA, GOG-0227C) have demonstrated clinical activity in previously treated metastatic endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC), respectively. Methods: A 3+3 phase I trial was conducted in patients with EC, platinum-resistant OC and CC who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose level (DL1) was NP at 125 mg/m2 with BEV at 50 mg/m2. There were 2 higher dose levels: DL2 (NP at 150 mg/m2 with BEV at 60 mg/m2) and DL3 (NP at 175 mg/m2 with BEV at 70 mg/m2). Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Disease evaluations were conducted after every 2 treatment cycles using RECIST criteria. Patients were treated until disease progression or intolerability. Samples were collected for pharmacokinetic (PK) studies. Results: Nine women 41 – 74 years of age (median 57) have enrolled (5 with EC and 4 with OC); data are available for the first 8. No DLTs have been observed among the 3 women enrolled on DL1, 3 women on DL2, and 2 women on DL3. All 3 patients on DL3 continue on treatment. The other 6 patients have discontinued due to adverse reactions (3), progression (2), and patient choice (1). The median number of cycles administered is 6 (4-14). The most common severe (G3/4) toxicities include neutropenia (37.5%) and leukopenia (25%). There have been 5 partial responses (62.5%): 1 on DL1 and 2 each on DL2 and DL3. PK evaluation is pending. Conclusions: AB160 therapy is safe and demonstrates promising clinical activity in patients with previously treated metastatic gynecologic malignancies. Further clinical testing is being pursued in this patient population. Clinical trial information: NCT02020707.

Objective Exercise is a cornerstone of therapeutic intervention for individuals with cystic fibrosis (CF). However, daily breathing treatments (e.g. chest physiotherapy and inhalation of nebulized albuterol) typically last ~90 minutes, providing a time‐barrier to completing daily exercise. Thus, the purpose of our study was to determine the effects of a combination therapy (exercise and nebulized albuterol) on airway function and bronchodilator delivery. We tested the hypotheses that combination therapy (exercise + nebulized albuterol) would 1) augment the bronchodilator effect compared to either intervention alone, and 2) increase the plasma concentration of albuterol compared to nebulized albuterol alone. Methods Participants with CF (n=9, 5 female, 25±2yrs, forced expiratory volume in 1 second (FEV 1 ) =82±5%predicted) first completed a screening visit (V̇O 2max test, cycle ergometer) and then three study visits in a randomized order. During each study visit, participants completed measures of airway function [FEV 1 and forced expiratory flow from 25–75% of forced vital capacity (FEF 25–75 )], and a blood draw (n=8) to determine plasma albuterol concentration. Participants then completed one of three interventions [albuterol only, (A): 2.5mg nebulized albuterol over 15min; exercise only (E): 30min cycling exercise at 50% of peak watts; albuterol and exercise (A+E): 30min cycling exercise at 50% of peak watts with 2.5mg nebulized albuterol nebulized over the last 15min of cycling). Airway function and plasma albuterol were measured at 0, 15, 30, 45, 60, 90, 120, 180, and 240min after the intervention. Additional plasma albuterol measures were taken 5, and 6hrs post intervention. Data are mean±SD. Results Delivery of nebulized albuterol during exercise did not augment or prolong the bronchodilator effect compared to exercise or albuterol alone. The transient improvement in airway function during the interventions—increase in FEV 1 (time=0.050, intervention p=0.166, interaction p=0.135) or increase in FEF 25–75 (time p=0.001, intervention p=0.207, interaction p=0.990) — was not different between the three interventions. Delivery of nebulized albuterol during exercise did not increase the plasma concentration of albuterol compared to nebulized albuterol alone. The maximum plasma concentration of albuterol (C max ) and the area under the curve (AUC) of albuterol concentration over time were not different between interventions (C max = 2.57±1.60 vs. 2.56±1.13ng·mL −1 , p=0.982; AUC 0–6hrs = 6.1±3.6 vs. 6.9±3.3hr·ng·mL −1 , p=0.188; A vs. A+E interventions, respectively). Conclusions Delivery of nebulized albuterol during moderate intensity exercise did not significantly alter bronchodilator effects or plasma levels of albuterol compared to albuterol or exercise alone. These data suggest that delivery of nebulized albuterol during exercise is safe and effective, but does not augment bronchodilator effects or drug delivery. This combination intervention (A+E) may be a time efficient method for individuals with cystic fibrosis to gain therapeutic effects of exercise and breathing treatments. Support or Funding Information F32 HL131151, Cystic Fibrosis Research Inc.

Abstract Background: Endx is a Tam metabolite with promising antitumor activity in Tam and aromatase inhibitor (AI) resistant estrogen receptor (ER) positive (+) metastatic breast cancer (MBC). Methods: This randomized phase II study compared progression-free survival (PFS) and toxicity of Endx 80 mg/day to Tam 20 mg/day in patients (pts) with ER+ MBC. Eligibility included postmenopausal women, ECOG PS 0-2, prior progression on AI but not Tam (unlimited endocrine therapy [ET] lines allowed), and a preregistration biopsy confirming ER+ (&gt;10% nuclear staining) and HER2-negative MBC. Stratified randomization was used balancing prior CDK 4/6 inhibitor (CDK 4/6i) use and/or everolimus (yes/no), measurable disease (yes/no) and endocrine resistance (primary/secondary) between arms. Pts randomized to Tam were allowed to cross over to Endx at progression. Due to short expected median PFS, differences in PFS were assessed using approaches for interval-censored data (ICD). 40 eligible pts were to be randomized to each arm so a one-sided alpha=0.10 generalized log-rank test (GLRT) would have a 90% chance of detecting a 50% decrease in hazard of disease progression with Endx (median: 6 months) relative to Tam (median: 3 months). Secondary endpoints include clinical benefit rate (stable or partial response &gt; 6 cycles) (CBR) for measurable and non-measurable disease. Pharmacokinetic (PK) data were obtained Day (d) 1 (4 hour), end of cycle 2, and at time of progression. Results: From March 2015 to March 2017, 108 women with endocrine refractory recurrent or MBC were preregistered. 27 pts did not register due to: biopsy demonstrating ER-/HER2- (3 pts), ER+/HER2+ (5 pts), cancer other than breast (3 pts), no cancer in specimen (6 pts), brain metastases (2 pts), acute infection (1 pt), progression on or recent use of Tam (2 pts), or pt refusal (5 pts). 4/81 pts who registered were excluded due to ineligibility (3 pts) or refusal to start protocol treatment (1 pt). The study cohort consisted of 40 pts randomized to Endx and 37 pts to Tam. The median (m) number of ETs in the metastatic setting was 2 (range 1-4) for each arm including prior CDK 4/6i (Endx: 42.5%, Tam: 29.7%) and everolimus (Endx: 35.0%, Tam: 40.5%). The m cycle number was 6 for Endx (range: 1-35) and 3 for Tam (range: 1-42). PFS for Endx was not significantly different compared to Tam (HR= 0.77; 95% CI: 0.49-1.22, GLRT p=0.309; mPFS: Endx 130 days [95% CI: 76-138 days] and Tam 42 days [95%CI: 24-129 days]). However, PFS was significantly longer in pts with no prior CDK 4/6i in the Endx arm (GLRT p=0.002; HR(no/yes)=0.31; 95%CI: 0.15-0.65) but not in the Tam arm (GLRT p=0.708) (unplanned analysis). Severe (grade (G) 3+) toxicities included: Endx G3 hypertriglyceridemia (3 pts); Tam: G3 hypertension with G2 stroke (1 pt), G3 thromboembolic event (1 pt), and G3 abdominal, bone and liver pain (1 pt). In Endx arm, d1 m Endx plasma concentration (conc) was 216 ng/ml (n=17; range: 144-400). For Tam arm, d1 m Tam conc was 17 ng/ml (n=17; range:11-23) (Endx not detectable). For the 25 pts that crossed over to Endx, CBR was 28.0% (90% CI: 14.0-46.2%) and 14 pts had pk data at progression. A lower median Endx conc (6 ng/ml range: 3.3-16.3) was observed in Tam patients at progression who then had Endx clinical benefit compared to Tam pts without clinical benefit after Endx crossover (median Endx 12 ng/ml; range 4.4-36.6).Conclusions: In endocrine-resistant breast cancer, Z-Endx was not significantly superior to Tam, but clinical benefit was observed in 28% that crossed over to Endx after Tam progression. In pts with no prior CDK 4/6i, the observation of significantly longer PFS in the Endx arm is hypothesis generating. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180820 (ECOG-ACRIN), https://acknowledgments.alliancefound.org; Clinical Trials.gov Identifier:NCT02311933 Citation Format: Matthew P. Goetz, Vera J Suman, Joel M Reid, Mary Kuffel, Sarah A Buhrow, Renee M McGovern, John Black, Travis Dockter, William F Symmans, Minetta C Liu, John R Hawse, James Doroshow, Anna M Storniolo, Jerry M Collins, Howard Streicher, Matthew M Ames, James N Ingle, Ann Partridge, Lisa Carey. A randomized phase II trial of tamoxifen versus Z-endoxifen HCL in postmenopausal women with metastatic estrogen receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-06.

e21521 Background: Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of pevonedistat has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for pevonedistat in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended phase 2 dose of pevonedistat in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: Using a rolling six design, we conducted a phase 1 trial of pevonedistat in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Results: 18 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 11 (61%) were male. Six pts had brain tumors, and 12 pts had solid tumors. Six pts each enrolled on pevonedistat dose levels 1 (15mg/m2), 2 (20mg/m2), and 3 (25mg/m2). There were no DLTs; DLT assessment is pending for 1 pt on dose level 3. Grade 3/4 toxicities included grade 4 lymphocyte count decreased (n = 2), grade 3 white blood cell decreased (n = 2), and 1 pt each with grade 3 anemia, elevated AST, and elevated ALT. The most frequent AEs were anemia (83%), nausea (61%), elevated AST (61%), and diarrhea (61%). Pharmacokinetic analysis is pending. Conclusions: Pevonedistat in combination with IRN and TMZ is well tolerated in pts with solid or brain tumors. PK and PD analyses are ongoing to establish the recommended dose. Clinical trial information: NCT03323034.

e21519 Background: Semaphorins regulate tumor progression, immune responses, and angiogenesis. SEMA4D was identified as a candidate proto-oncogene by a Sleeping Beauty forward genetic screen that induced osteosarcoma in mice. SEMA4D is expressed on tumors, including osteosarcoma, and in the tumor microenvironment. VX15/2503, a humanized IgG4 monoclonal antibody, binds SEMA4D, blocks receptor interaction and enhances the anti-tumor immune response in preclinical studies. This trial aimed to determine the tolerability and recommended dose of VX15/2503 in patients with relapsed/refractory solid tumors and activity in patients with osteosarcoma. Methods: Part A enrolled patients age≤ 21y with refractory solid tumors to assess the tolerability of VX15/2503 (20 mg/kg) IV every 14 days x 2 doses/cycle. The recommended dose was one that was tolerated and achieved sustained target saturation. Up to 6 additional children were enrolled to assess pharmacokinetics (PK). In part B, a two-stage design was used to assess the activity of VX15/2503 in patients with measurable, relapsed /refractory osteosarcoma. In part B1 patients > 21-30y accrued concurrently with part A; Part B2 (patients £ 21y) was initiated after the pediatric recommended dose was determined. Correlative studies including target saturation by VX15/2503 were required. Results: 18 eligible patients enrolled, 16 evaluable for toxicity. In part A (n = 12) the median (range) age was 12.5 (1-20) y. Diagnoses included osteosarcoma (8), neuroblastoma (2), other (2). No dose limiting toxicities (DLTs) were observed. In Part B1, (n = 6) median (range) age was 22.5 (22-30) y; one patient had cycle 1 DLTs (grade 3 acute kidney injury, creatinine increase, arthralgia and myalgia); a second patient had a later cycle DLT (grade 4 pericardial effusion). Given only 1/18 had a cycle 1 DLT, this did not impact dose selection. T-cell saturation by VX15/2503 was adequate and sustained in all patients. Conclusions: VX15/2503 was well tolerated at 20 mg/kg IV every 2 weeks and is the recommended dose in children, adolescents and young adults. The activity in osteosarcoma is under evaluation. Future trials combining VX15/2503 with novel agents are in development. Clinical trial information: NCT03320330.

e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/m2 and SAHA 100 mg b.i.d (dose level 3). Median number of previous treatment regimens was 3 (R:1-6). Dose limiting toxicities (DLT) were seen in 2/2 pts at dose level 1: grade 4 thrombocytopenia (1 pt), grade 3 nausea, vomiting and fatigue (2 pts), and grade 5 hepatic failure (1 pt). Two of six patients at dose level 2 experienced DLT: grade 3 fatigue (1 pt) and worsening of pre-existing Sweet’s Syndrome (1 pt). Common AEs (G1/2) included fatigue (73%), cough (64%), anorexia (55%), and injection site reaction (45%). One minor response was seen and 5 pt had prolonged stable disease (>16 weeks), including one patient for 88 weeks. Analysis of post-treatment tumor biopsies showed demethylation of EBV lytic cycle gene promoters after treatment. SAHA PK, IHC results for EBV gene expression in tumor tissue, EBV viral load and characterization of circulating EBV will be presented. Conclusions: 5AC/SAHA appears to be tolerable at dose level 3 with suggestion of clinical benefit. Analysis of post-treatment tumor and blood samples suggests that modulation of EBV gene expression may play a role in the mechanism underlying clinical benefit. Continued accrual at dose level 3 is ongoing. Clinical trial information: NCT00336063.