Goh, Boon Cher

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6–50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: −86.8%; interquartile range [IQR]: −90.7% to −70.9%) compared with the 28 who did not (median: −69.0%; IQR: −78.1% to −27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (−23.5% [CI: −55.3 to 8.3]; Fisher's exact test p -value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.

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.

e14507 Background: Regorafenib, an oral multikinase inhibitor of VEGFR2/3, PDGFRb, KIT, FGFR, RET, RAF and TIE2, is efficacious in refractory mCRC but its mechanism of action is unclear and predictive biomarkers are lacking. Methods: We assessed tumor and circulatory biomarkers in a phase 2 study of regorafenib in refractory mCRC patients. Regorafenib was administered orally at 160mg/d for 3 out of 4 weeks. Post cycle 2 response was assessed by RECIST 1.1. Subjects were scheduled for FDG PET-CT scans (pre + D15) and paired core needle tumor biopsies for IHC analysis (pre + D21) in cycle 1. Archival tumor mutations were evaluated using Sequenom MassARRAY OncoCarta Panel V1.0 assay. Results: 35 patients were treated; 49% received > 4 prior therapies and 43% had prior bevacizumab. Median PFS was 3.45 mths (95% CI: 3.40-3.49), ORR was 3% and disease control rate [DCR] (PR + SD at 8 wks) was 57%. Early PET responses (EORTC criteria) were seen in 49%, but did not predict for DCR (p=1.0). Fatigue, hand foot skin reaction (HFSR), voice change and diarrhea occurred in > 30% of subjects. Grade 3-5 toxicities occurred in 46%, the commonest being HFSR and rash (17% each). Median relative dose intensity was 92%; 43% required > 1 dose reduction, 60% required > 1 dose interruption. KRAS (29%), BRAF (9%), EGFR (9%), NRAS (6%) KIT (3%), PIK3CA (3%), PDGFRA (3%) and CDK (3%) mutations were detected in archival tumors. None predicted for ORR or DCR; PFS was identical in KRAS mutant vs wt patients (3.45 mths, p=0.39) and similar in BRAF mutant vs wt patients (3.48 vs 3.45 mths, p=0.10). The patient with the longest PFS (12.6 mths) had a BRAF mutation. Amongst the 10 paired tumor samples available, IHC markers upregulated in >50% cases were pMEK, pERK, pJun and pJNK, whilst those downregulated/ unchanged in >50% were pKIT, pVEGFR2, CD31 [vascular endothelial cells (ECs)] and podoplanin (lymphatic ECs). The greatest change was observed in podoplanin expression, corresponding to a 60% reduction in lymphatic vessel density. Conclusions: FDG-PET responses in cycle 1 did not predict for regorafenib clinical benefit in mCRC patients. Targeting lymphatic/vascular ECs in the tumor microenvironment may be a more significant antitumor mechanism of regorafenib than MAP kinase pathway inhibition. Clinical trial information: NCT01189903.

5544 Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true tumor response rate is >5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, >18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg at entry, QTc interval <480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.

Abstract Background: Endemic nasopharyngeal carcinoma (NPC) refers to non-keratinizing (NK) subtypes harboring Epstein Barr virus (EBV) that frequently express programmed death-ligand 1 (PD-L1). We recently reported ≥30% of NPC harbor MHC class 1 gene alterations in a whole genome study. Method: We investigated the activity of nivolumab (NIVO) & relationship with PD-L1 & HLA expression (exp) in tumor cells (TC) & tumor infiltrating cells (TIL). Eligible patient (pt)s had to fail ≥ 1 prior line of platinum-based chemo. NIVO (3mg/kg IV, q2 weeks) was given until disease progression (PD). Archived tumors were analyzed for PD-L1 (DAKO) & HLA mutations (indicated by loss of HLA-A &/or B exp). Result: A total of 45 pts were enrolled across 11 sites from Oct 2015 to June 2016. Overall, 43 and 44 pts were evaluable respectively for response rate (RR, RECIST) & adverse events (AE). The median age was 57 years, 77% pts were males & 84% were Asians. The median number of prior chemo was 3 (range 1-9 lines). Of the 43 evaluable pts, there were 8 confirmed (19%, 95% CI: 8-33%) & 1 unconfirmed partial response (PR), 17 PD (40%), 14 stable disease (SD, 33%) & 3 pts were not assessed. One pt (MD015-027) had an unconfirmed clinical CR in an occipital metastasis (met). Pts received a median of 3 cycles of NIVO (range 1 - 14). Median overall survival has not been reached yet. Of the 44 pts evaluable for AE, 8 (18.2%) had grade 3 or higher treatment-related AEs & 1 pt died of sepsis. The most common grade 3 or higher AEs were increase in alanine/aspartate aminotransferase (n=3), & 1 pt respectively for hyponatremia, neutropenia, fatigue & diarrhea. Of the 21 tumor samples analyzed, 11/21 (52%) had &gt;1% PD-L1 expressed mainly in TC. Table 1 outlines relationship between RR & PD-L1 exp. All pts with PR had &gt;5% PD-L1 exp & one pt (34003-022) with CR (nasopharynx) & PR (lung mets) had the highest exp (80%). Majority of pts with PD had &lt;1% PD-L1 exp tumors. One primary progressor (34003-032) had a PD-L1 +ve tumor harboring a complete loss of HLA-B signal (TC), but intact signal in TILs & stromal cells. Conclusion: NIVO is active in this heavily pre-treated group of pts with NK-NPC and longer follow-up is needed for survival endpoints. Preliminary result suggests PD-L1 exp may predict benefit from NIVO. The analytical result of all 45 tumors will be presented. Table 1.PD-L1 exp and RECIST response in 21 ptsPD-L1%espRR%PRSDPD0-11&lt;1%-265%24-10%--120%-1-30%11-80%1--Total498 Citation Format: Brigette B. Ma, Boon Cher Goh, Wan T. Lim, Kwok W. Lo, Edwin P. Hui, Jonathan W. Riess, Mark Agulnik, Alex Y. Chang, Julie A. Kish, Dean W. Lim, Douglas R. Adkins, Kevin J. Cullen, Barbara J. Gitlitz, Nathan R. Foster, Adam M. Pettinger, Sanna Mckinzie, Ka F. To, Brian Costello, Howard Streicher, Anthony T. Chan. Multicenter phase II study of nivolumab in previously treated patients with recurrent and metastatic non-keratinizing nasopharyngeal carcinoma - Mayo clinic Phase 2 Consortium P2C-MN026, NCI9742, NCT02339558 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT076. doi:10.1158/1538-7445.AM2017-CT076

259 Background: Belinostat is a novel histone deactylase inhibitor which demonstrates preclinical activity in HCC. We report the results of a phase I/II study on belinostat in patients (pts) with unresectable HCC. Methods: Major eligibility criteria included histologically confirmed HCC not amenable to curative treatment; PS ≤ 2; adequate organ function; prior systemic therapy was allowed. In the phase I portion, belinostat was given i.v. on D1-5 every 3 weeks with dose levels of 600, 900, 1200 and 1400 mg/m2/day. In the phase II portion, belinostat was tested at the MTD. Primary endpoint was PFS and secondary endpoints were RR according to RECIST and OS. CT assessment was done every 8 weeks. Results: Phase I portion: a total of 18 pts were accrued; no DLTs were observed at 1400mg/m2/day for 5 days, and this dose was selected for phase II development. Phase II portion: 42 pts were accrued; Median age = 57.5 years; 41 had Child’s A function, and 24 pt had ECOG 0. Sixteen (38%) had previous systemic therapy, and 21 (50%) had previous transarterial therapy. Median follow-up was 20.0 months. The PR and SD rate was 2.4% (1/42) and 45.2% (19/42). Median PFS was 2.64 months (95%C.I. 1.55-3.17) and OS was 6.60 months (95%C.I. 4.53-11.60). Grade 3 or higher toxicities (>5% rate) were abdominal pain (9.5%), (9.5%) hyperbilirubinemia (9.5%), raised ALT (9.5%); anemia (7.1%) and vomiting (7.1%). Conclusions: Belinostat demonstrates disease stabilization in a predominantly pretreated population of pts with unresectable HCC with an acceptable safety profile. Further randomized studies are warranted.Supported in part by N01-CM-62205.

Abstract Background: NPC is endemic to Asia and over 40% of cases harbor PIK3CA amplification. MK2206 is an allosteric AKT inhibitor with activity in NPC in vitro. Methods: Pts who had progressed after palliative chemotherapy (chemo) for metastatic or recurrent NPC, received oral MK-2206 at 200 mg on Days 1, 8, 15 & 22 of each 28-day cycle until disease progression. Plasma samples were collected at serial time points during cycle 1 for EBV DNA analysis, archived tumor samples were collected where feasible. The primary dual endpoints (2-stage design) consisted of RECIST-defined tumor response rate (RR) and 6-month (m) progression-free survival (PFS) rate. Secondary endpoints were overall survival (OS), PFS and adverse events (AEs). Results: Of the 21 pts enrolled, the median age was 47 years (range: 32-67), 91% were male, 81% had prior radiotherapy and 81% had &gt; 1 prior line of palliative chemo. At the time of analysis, 20 out of 21 pts have ended treatment. The best responses were: 1 partial response (PR, 5%) lasting 4 ms; 10 stable disease (SD, 50%), 9 progressive disease (PD, 45%). The 6-m PFS rate was 38.9% (95% CI: 18.1-59.3%) and median PFS was 2.7 ms (95% CI: 0.9-7.2 ms). The 6-m OS rate was 67.9% (95% CI: 41.8-84.1%) and median survival has not been reached. In 7 pts who had SD more than or equal to 6 ms, the duration of treatment ranged from 6.4-13.9 ms. Of the 21 pts evaluable for AEs, 12 pts (57%) had at least one grade 3 AE [[Unable to Display Character: &#8211;]] macular rash (6 pts - 29%), dysphagia (2 pts - 10%), hyperglycemia (2 pts - 10%) (see Table 1). The tumor samples of 7 pts were analyzed by FISH; 3 showed PIK3CA amplification, including 1 pt with chromosome 3 polysomy. Amongst these pts, 1 had SD more than 6ms, 1 had SD more than 12 ms, and 1 is still on treatment. Pts who had SD less than 6 m or PD did not have PIK3CA amplification. Conclusions: MK2206 is well tolerated and has signs of activity in unselected pts with NPC. Preliminary results suggest that PIK3CA amplification may be related to prolonged disease stabilization from MK2206, and analysis for other PIK3CA gene alterations in more samples will be undertaken. Result of the plasma EBV DNA result will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B273. Citation Format: Brigette B. Ma, Boon Cher Goh, Wan Teck Lim, Eng Huat Tan, Gilberto de Lima Lopes, Edwin P. Hui, Ann D. King, Kwok Wai Lo, Herbert Loong, Leung Li, Nathan Foster, Michael Kam, Sing Fai Leung, Charles Erlichman, Anthony TC Chan. Multicenter Phase II study of MK-2206 in previously treated patients (pts) with recurrent and metastatic nasopharyngeal carcinoma (NPC): Mayo Clinic Phase II Consortium (Protocol: MC1079). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B273.