Citations

3539 Background: Therapy with decitabine and entinostat (ENT: HDAC inhibitor) shows synergistic effect in re-expression of tumor-suppressor genes and growth inhibition in CRC cell lines and in vivo studies. Methods: We conducted a phase II, multi-institutional study of SQ 5-azacitidine (AZA) and oral ENT in mCRC pts. A 28 day cycle included: AZA at 40 mg/m2 d1-5 and 8-10 with ENT 7 mg d3 and 10. Initial eligibility criteria included: ECOG PS 0-1, good end organ function, and biopsiable disease for cohort A (CoA). An interim analysis indicated that toxicity which crossed pre-specified safety boundary was secondary to disease. A 2nd cohort B (CoB) with eligibility restrictions: <2 prior regimens in KRAS-mutated CRC pts, <3 prior regimens if KRAS wild-type, and liver disease limited to <30% of volume was accrued. Serial tumor biopsies and research blood were collected to assess for methylation/expression changes in circulating tumor DNA and biopsies, respectively. The primary endpoint was response as measured by RECIST criteria using a 2-stage Simon design. Results: 47 pts were initially enrolled (24 CoA, 23 CoB). Pts received a median of 2 cycles on both cohorts (1-16 CoA, 2-6 CoB). Pts had a median of 4 prior therapies for CoA (range 2-9) and 3 for CoB (range 2-6). Gr 4 AEs attributable to treatment for CoA included hyperglycemia (1) and hypokalemia (1); other common Gr 3 AEs included anemia (3), decreased lymphocytes (7), fatigue (3), and nausea (3). CoB pts experienced grade 3 chest pain (1), neutropenia (2), leucopenia (2), urinary tract obstruction (1), and hypophosphatemia (1). No responses have been observed. Results of translational objectives will be presented at the meeting. Conclusions: SQ AZA and ENT therapy does not have clinical activity as defined by confirmed response in aCRC. Follow-up for survival, response to subsequent therapy, and correlative analysis are ongoing. Supported in part by N01-CM-2011-00099. Clinical trial information: NCT01105377. [Table: see text]

9504 Background: CCI-779 inhibits the mammalian target of rapamycin (mTOR), a Ser/Thr kinase involved with the initiation of mRNA translation, showing growth inhibition in many tumor cell types. The primary goal was to evaluate the confirmed response rate (RR) of CCI-779 in advanced STS. Methods: Eligibility included pts ≥ 18 yrs, measurable advanced STS, PS 0–2, adequate laboratory function (including Chol ≤ 350 mg/dL and TG ≤ 400 mg/dL), no prior chemo for advanced disease (adjuvant chemo allowed), and no brain metastases. Following premedication with an antihistamine, CCI-779 was given intravenously at 25 mg over 30 minutes on days 1, 8, 15, and 22, repeated q 4 wks. A total 50 pts were to be enrolled, if there were 2 responses at the time of an interim analysis conducted on the initial 20 patients. Pre- and post-treatment blood was collected to evaluate p70S6 kinase, S6 phosphorylation, inhibition of mTOR, and sirolimus levels. Pre-treatment paraffin-embedded tumor tissue was used to evaluate immunohistochemistry markers (including, EFGR, c-Myc, Her2, 4EBP1). Results: 41 eligible pts (18 male, median age 62 yrs with range 28–79) were enrolled from 11/04 to 9/05. 71% presented with high grade tumors. Histologic subtypes include: malignant fibrous histiocytoma (MFH) (7), sarcoma NOS (9), fibrosarcoma NOS (3), liposarcoma NOS (5), leiomyosarcoma (8), endometrial stromal (1), synovial (1), hemangio/angiosarcoma (2), hemangiopericytoma NOS (1), and neurofibrosarcoma (1). 42% (16/38) evaluable pts had Gr 3+ events at least possibly related to CCI-779, 1 of which was Gr 4 hyperglycemia (see table). One pt having extremity fibrosarcoma, achieved a PR after 2 cycles lasting at least 36 weeks. Twenty-eight pts have progressed and 10 have died. Estimated median time to progression is 2 months (95% CI 1.8–3.5). Conclusions: Despite an acceptable toxicity profile, CCI-779 failed to demonstrate promising activity in pts with advanced STS. Results of the correlative studies are pending. Supported by N01 CM17104. [Table: see text] No significant financial relationships to disclose.

4043 Background: Systemic treatment options for progressive metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express the epidermal growth factor receptor (EGFR). Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NET cell lines. Methods: Eligibility criteria included: radiographic progression by RECIST criteria, ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior interferon and prior or concurrent octreotide (if disease progression documented on stable dose) were allowed. Pts received gefitinib 250 mg po daily. We evaluated 6 month (mos) progression-free survival (PFS) in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. 6 mos PFS rates of 30% (CT) and 10% (ICC) were considered promising. Results: 96 pts were enrolled: (57 CT, 39 ICC). For pts evaluable for the primary endpoint, 23 of 38 (61%) CT pts and 9 of 29 (31%) pts with ICC were progression-free at 6 mos. 1 PR and one minor response (MR = 20–29% decrease in sum of target lesion diameters) were observed in 40 CT pts; 2 PR and 1 MR in 31 ICC pts. In addition, 32% (12/38) of CT and 14% (4/29) of ICC pts had stable disease on study for a duration that exceeded by at least 4 months the time to progression documented prior to study entry. Grade 3–4 toxicity was infrequent with fatigue (6%), diarrhea (5%) and rash (3%) most common. Evaluation of markers of the EGFR pathway on tumor tissue will be presented. Conclusions: Gefitinib is well-tolerated and results in prolonged disease stabilization in pts with prior documented objective progression of CT and ICC, with rare objective responses. Supported by NOI CM17104. No significant financial relationships to disclose.

14118 Background: Triapine is a small molecule iron chelator that has been shown to inhibit ribonucleotide reductase (RR) at the M2 subunit. Early trials suggested activity in pancreatic cancer. The P2C initiated a study of single agent Triapine as both first-line therapy and for pts with gemcitabine-refractory disease. Correlatives included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy (EPR). Methods: Standard eligibility criteria were used, however, pts with G6PD deficiency were excluded. Triapine was given 96 mg/m2 IV over 2 hours, days 1–4 and 15–18, repeated q 28 days. Primary goals - evaluate survival (S) at 6 mos (previously untreated pts) and 4 mos (refractory pts). Interim analyses were planned when 28 previously untreated and 20 refractory pts were enrolled. Results: 14 eligible pts were enrolled in 10 mos (13 refractory, 9 male). The previously untreated pt received only 1 cycle secondary to progressive disease. Of the 13 refractory pts, 7 pts received at most 2 cycles; 6 received 1. Disease progression precluded further treatment in 11 pts. 6 pts had Gr 4 toxicities at least possibly related to drug, including: neutropenia-4, hyperkalemia-1, hyponatremia-1, leukopenia-1, thrombocytopenia-1, hypophosphatemia-1. 6 pts had a Gr 3 fatigue. One refractory patient expired on study. No responses were seen. Estimated 4 mos S in refractory pts is 16% (95% CI 3–94). EPR studies showed that Triapine led to a loss of the RR tyrosine radical EPR signal. Conclusions: Enrollment was suspended due to excess toxicity and lack of activity in pts refractory to gemcitabine. Correlative studies confirm the mechanism of action of Triapine as a chelating agent on RR. Supported by NCI Grant N01 CM17104 and the NCI Translational Research Fund. No significant financial relationships to disclose.

4504 Background: Treatment options for metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor receptor-β (PDGFR-β). Sorafenib, a small-molecule inhibitor of the VEGFR-2 and PDGFR-β tyrosine kinase domains, is a rational targeted therapy to evaluate in NET. Methods: Eligibility criteria included: ECOG PS = 2, = 1 prior chemotherapy, good organ function and signed informed consent. Prior interferon and prior or concurrent octreotide at a stable dose were allowed. Pts unable to take oral medications, with uncontrolled hypertension or with symptomatic coronary artery disease were excluded. Pts received sorafenib 400 mg po BID. Primary endpoint was response by RECIST in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. Results: 93 pts were enrolled: (50 CT, 43 ICC). For pts evaluable for the primary endpoint, 4 of 41 (10%) CT pts and 4 of 41 (10%) ICC pts had a PR. There were 3 minor responses (MR = 20–29% decrease in sum of target lesion diameters) in CT pts and 9 MRs in ICC pts for PR+MR rate of 17% for CT pts and 32% for ICC pts. For pts evaluable, 6-month progression-free survival was observed in 8/20 CT and 14/23 ICC pts. Grade 3–4 toxicity occurred in 43% of pts, with skin (20%), GI (7%) and fatigue (9%) most common. Translational studies from tumor tissue will be presented. Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade = 3 toxicity. Supported by NOI CM6225. No significant financial relationships to disclose.

Abstract Background: Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor signaling pathway, a pathway critical to the survival and proliferation of malignant B cells. Ibrutinib, a small molecule inhibitor of BTK, has shown significant activity in several B-cell malignancies and is currently FDA approved for the treatment of patients (pts) with CLL or mantle cell lymphoma who have received at least one prior treatment.In a Phase 1 dose-escalation study, ibrutinib induced a response in 6 (38%) of 16 patients (pts) with relapsed/refractory FL and 6/11 (54%) of pts treated at doses ≥ 2.5 mg/kg (Advani JCO 2013, Fowler ASH abstr 156:2012). 560 mg daily was identified as a well-tolerated dose in lymphoma resulting in full-target occupancy. On the basis of these results, the Mayo Clinic and Princess Margaret P2Cs conducted a CTEP-sponsored Phase 2 trial of single-agent ibrutinib in relapsed/refractory FL (NCI 9271). Methods: Eligible pts had relapsed or refractory FL (Gr 1, 2, or 3a) that had progressed during or after 1 or more prior chemotherapy regimens. Therapy consisted of ibrutinib, 560 mg daily, until progression or unacceptable toxicity. Response was assessed by CT at 8 weeks and then every 12 weeks. All pts were required to have an on-study biopsy and a second biopsy at progression after response with fresh tissue collected for correlative studies. The primary endpoint was overall response rate (ORR) and secondary endpoints were safety and tolerability, overall survival, time to response, time to treatment failure, duration of response, and progression-free survival (PFS). Planned exploratory correlative studies included C1D8 and C3D1 FDG-PET response evaluation in a subset of 20 patients, and whole-transcriptome sequencing for correlation of mutations with response and resistance. Results: 40 patients (38 evaluable for response) were accrued from April 2013 to April 2014. Median age was 64 years (range 46-82), 70% were men, 55% had FLIPI ≥ 3, median number of prior regimens was 3 (range 1-11), 20% had a prior stem cell transplant, 45% were rituximab refractory, and 36% were refractory to their most recent treatment. At a median follow-up of 6.5 months (mo) (range 1.8-14.6+), the ORR for the 40 intention-to-treat pts is 30% (95% CI: 17-47%) with 1 CR and 11 PRs by CT criteria (4/12 responders had a negative restaging PET/CT). 26 (65%) patients have exhibited tumor size reduction. Only 2/18 (11%) pts with rituximab-refractory disease responded, compared to 8/19 (42%) pts with rituximab-sensitive disease (P=0.06) and 2/3 who were rituximab-naïve. There was no correlation between response and number of prior regimens. Median time to response was 2.4 mo (range 1.8-12.9 mo). Median PFS is 9.9 mo (95% CI: 6 mo, not reached). One of 12 responders has progressed after 9.9 mo on treatment. Median treatment duration was 5 mo (range 1-15+ mo). Dose delays (2 pts) and reductions were infrequent (4 pts). 17 pts have discontinued treatment due to PD (12), refusal (2), AEs (2), and death (1). Gr 3-4 AEs occurred in 30% of pts, including the following AEs in more than 1 pt: anemia (2), neutropenia (3), and infection (2). 3 pts have died (1 PD, 1 pneumonia, 1 gastric hemorrhage). Of the 20 pts with C1D8 PET scans, 19 also had C3D1 PET scans and were evaluable for response. Six of these 19 pts had objective responses by CT criteria at week 8 or beyond. Of the 6 responders, C1D8 PET/CT showed qualitative (visual) improvement in 3 pts, no visual change in 1 pt, and qualitative worsening in 2 pts. On the C3D1 PET/CT, 4 of 6 had qualitative improvement and 2 had no change. Evaluation of quantitative PET data including SUVs and total lesion glycolysis is ongoing and will be presented. Conclusions: Single agent ibrutinib is well tolerated with a modest ORR in relapsed/refractory FL at this early assessment. Continued follow-up is warranted to capture late responders and to establish response duration. Ibrutinib appears less active in FL than in MCL and CLL. Early PET scans (C1D8) do not reliably predict for response. Support by N01-CM-2011-00099 Disclosures Bartlett: Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Research Funding; Janssen: Research Funding; ImaginAb: Research Funding; Genentech: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Celgene: Research Funding. Off Label Use: PF-05082566 for B-NHL. Kuruvilla:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Background: Myelofibrosis with myeloid metaplasia (MMM) is a progressive and fatal myeloproliferative disorder with limited therapeutic options. R115777 is a non-peptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) which we recently reported has in vitro activity against aberrant myeloid progenitors from MMM patients (Leukemia2003;17:849). This observation, coupled with the clinical activity demonstrated in high risk acute myeloid leukemia (Blood2001;97:3361) and chronic myeloid disorders (Blood2003;101:1692) led us to perform a Phase II trial in patients (pts) with MMM. Methods: Eligible pts had histologically confirmed MMM and were symptomatic, defined by anemia (hemoglobin<10g/dL or transfusion dependent) or palpable hepatosplenomegaly. Pts received 300 mg of R115777 orally twice daily for the first 21 days of a 28 day cycle. Dose escalations (up to 1200mg/day) and reductions (down to 100mg/day) were allowed based on activity and toxicity. The primary endpoint was response as defined by improvement in either anemia or organomegaly. Results: 34 pts (median age 65 yrs, range 55–80; 71% male) were enrolled in the trial. All pts displayed symptomatic disease at enrollment, with 10 who were erythrocyte transfusion dependent; and 19 (56%) had a Lille MMM prognostic score ≥1; no pts were significantly thrombocytopenic at entry by enrollment criteria. Median pre-study spleen and liver sizes were 12 cm (range: 0–35) and 2 cm (range: 0–15) below the left and right costal margin, respectively. Median time to discontinuation of therapy was 5.5 months (95% CI:2.9–6.4). Reasons for early termination were progression (7), adverse reactions (5), co-morbidities (2), refusal of further treatment (2), and death on study (1). One pt died of grade 5 pneumonitis two weeks after study enrollment, which was felt to be unrelated to study treatment. Significant toxicities (≥ grade 3) were seen for myelosuppression (n=13), neuropathy (n=2), fatigue (n=1), rash (n=1) and hyponatremia (n=1). Overall, R115777 resulted in little improvement in anemia, with the exception of one anemia-based partial response. However, the myelosuppressive aspects of the agent may have masked improvements in cytopenias. In contrast, R115777 did result in clinically relevant decreases in organomegaly in 11 pts (33%) (splenomegaly in 3 pts, hepatomegaly in 5 pts, and both in an additional 3 pts.) Across all pts who had some reduction in splenomegaly, the median maximal reduction was 42.5% (of palpable component; range: 8–100%). Likewise, all patients with baseline hepatomegaly had resolution of this problem at some point during therapy. Four pts remain on the agent (from 14 to 22 months) for continued and sustained improvement in organomegaly. Responses observed did not significantly correlate with reductions in bone marrow fibrosis, osteosclerosis, neoangiogenesis, or resolution of baseline karyotypic abnormalities. Conclusions: R115777 has demonstrated preliminary activity against MMM associated organomegaly. Whether this latter benefit is independent of R115777 induced myelosuppression is unclear. The myelosuppression observed was generally mild and without clinical consequence, although it was difficult to differentiate between myelosuppression versus disease progression. Pts continue to be followed to evaluate durability of observed responses, long term effects on anemia and intramedullary manifestations of the disease.

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

245 Background: Gemcitabine (GEM) monotherapy for PDA has modest activity. 17-N-Allylamino-17-demthoxygeldanamycin (Tanespimycin/17AAG), is an HSP90 inhibitor, which results in degradation of a number of client proteins such as RAF and Akt. Arlander et al (J Biol Chem. 2003 278:52572-7) have demonstrated that 17AAG targeting of HSP90 leads to Chk1 degradation. Chk1 is upregulated with GEM treatment which affects cell survival (Karnitz et al. Mol Pharmacol. 2005 68:1636-44). In vitro, the combination demonstrated in vitro synergy. Thus the potential clinical activity in pancreatic cancer of the combination was explored. Methods: A phase II multicenter prospective study was performed using GEM 750 mg/m2 d1,8 and 17AAG 154 mg/m2 d2,9 on a 21 day cycle, as defined in a previous phase I trial. Patients with stage IV PDA, with adequate liver, kidney function and counts, ECOG 0-2 and no prior therapy for metastatic disease were eligible. The primary endpoint of 60% overall survival at 6 months was considered of clinical interest. Sixty-six patients were planned for accrual, and an interim analysis was planned after 25 evaluable patients. Informed, written consent was obtained from all pts. Results: Due to lack of drug availability and failure to achieve the planned endpoint, accrual was halted at 21 pts, enrolled from 5/08 to 9/10, of which 20 were evaluable (1 cancelled prior to treatment). Median age was 61.5 yrs., 55% were male, PS 0 (50%), 1 (45%), 2 (5%); 95% were non-Hispanic white, 1 was African American. Two had received adjuvant therapy for PDA. Tolerability was moderate, with 13 pts (65%) having > grade 3 adverse event (AE), with 15% gr 4 AEs and 0% gr 5. Nausea (20%), vomiting (20%), constipation (15%), dehydration (15%), and anorexia (10%), were the most common non-heme AEs. Lymphopenia (15%), leukopenia (10%) and neutropenia (10%) were common grade 3 hematologic AEs. No complete or partial responses were seen. 40% of patients were alive at 6 months, with a median OS of 5.4 months. Conclusions: HSP 90 inhibitor 17AAG in combination with GEM does not show activity for treatment of PDA. Further trials should not be pursued with this combination. Supported by N01-CM-62205. Clinical trial information: NCT00577889.