PO QD Research Articles

Phase II study of apatinib combined with vinorelbine in second-line treatment failure non-driver gene mutation advanced non-small cell lung cancer (NCT03652857).

e20669 Background: There is currently no standard treatment strategy for non-driver gene mutation advanced non-small cell lung cancer (NSCLC) patients experiencing progression after two or more lines of chemotherapy. Our study assessed the efficacy and safety of apatinib combined with vinorelbine in non-driver gene advanced NSCLC patients for whom at least two lines of prior chemotherapy had failed. Methods: This is a Phase II, single arm clinical trial. 30 advanced NSCLC patients who had two or more prior lines of chemotherapy had failed enrolled in this study. All the patients received treatment of apatinib 500mg, po qd plus vinorelbine 60mg/m2 po qweek. The primary endpoint was overall response rate (ORR). Secondary endpoints were overall (OS), progression-free survival (PFS), disease control rate (DCR) and safety. Results: Between January 2016 and November 2018, 30 patients were enrolled. 25 patients finished all the treatment. 5 patients discontinued the treatment for adverse events. The ORR of all the patients was 36.3 %( 11/30). The DCR of all the patients was 76.3 %( 23/30). The median PFS of all the patients was 4.5months (95% CI 2.4-6.6m). The median OS of all the patients was 10months (3.8m-16.2m). The most common grade 3 to 4 adverse events were non-hematologic including hand-foot syndrome. Moreover, medicine reduction seem not be an important role in disease prognosis. Conclusions: These data show that apatinib combined with vinorelbine can be a good choose with an acceptable safety profile in non-driver gene mutation advanced NSCLC patients refractory to two or more lines of prior chemotherapy. Clinical trial information: NCT03652857.

Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma.

2020 Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate conditionally expressing IL-12 under the control of veledimex (V) acting via the proprietary RheoSwitch Therapeutic System (RTS) gene switch with a therapeutic window. Intratumoral Ad + oral V monotherapy (Phase 1 study, NCT02026271 ) resulted in a new sustained intra-tumor influx of activated cytotoxic T cells, consistent with an immune-mediated anti-tumor effect improving median overall survival (mOS) of subjects with recurrent glioblastoma (rGBM). This correlated with an increased circulating CD8+/FoxP3+ T cell ratio (“cytoindex”), an emerging biomarker for mOS. PD-1 expression on infiltrating T cells at biopsy after Ad+V, supports combining controlled IL-12 with a PD-1 inhibitor to further augment T-cell-mediated anti-tumor effects. The rationale is also supported by increased OS (100% combo vs 63% for Ad+V vs 40% for anti-PD-1) in mice bearing GL-261 glioma. Methods: An ongoing open label, dose-escalation Phase 1 trial (NCT03636477) is evaluating safety and tolerability of local, controlled IL-12 with nivolumab (nivo) in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles, Day 0) plus V (10-20 mg) PO QD x 15 with nivo (1-3mg/kg) IV on Days -7, 15, then Q2W. Results: Safety data revealed a similar profile as Ad +V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with anti-PD-1 reports. ARs were manageable and reversible with no synergistic toxicities. Nivo alone did not alter peripheral IL-12 levels (median baseline (before anti-PD-1) 0.9 pg/mL; Day 0 1 pg/mL) increasing to 5.5 pg/mL on Day 3. Nivo alone increased peripheral T cells (CD3+CD8+ median baseline 23%; Day 0 26%) and Ad+V elevated peripheral CD3+CD8+ to 31% at Day 14. Nivo alone decreased regulatory T cells (FoxP3 baseline 1.5% vs Day 0 0.8%). Ad+V decreased these to 0.3% (Day 14). Combination therapy improved the cytoindex (baseline 15; Day 0 29; Day 14 80). Conclusions: Controlled IL-12 production using Ad + V with nivo is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile, warranting continued investigation in rGBM. Clinical trial information: NCT03636477.

Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): First interim BYLieve study results.

1040 Background: In the phase 3 SOLAR-1 study, ALP + fulvestrant (FUL) improved PFS in pts with HR+, HER2– ABC with a PIK3CA mutation overall and in the small group of pts with prior cyclin-dependent kinase 4/6 inhibitor (CDKi) use. We report interim data from the BYLieve study in pts with PIK3CA-mutated ABC and prior CDKi exposure. Methods: BYLieve is an ongoing, phase 2, open-label, non-comparative study of ALP 300 mg QD + ET in men and women with PIK3CA-mutated HR+, HER2– ABC whose disease progressed on/after CDKi + ET. Pts are permitted ≤2 prior anticancer therapies and ≤1 prior chemotherapy regimen for ABC. Pts with prior CDKi and AI ( FUL cohort) receive ALP and FUL 500 mg Q28d + C1d15 IM. Pts with prior CDKi and FUL ( LET cohort) receive ALP and letrozole (LET) 2.5 mg PO QD. In this preplanned interim analysis, conducted after ≥20 pts in FUL had ≥6 mo of follow-up, descriptive data are reported for preliminary safety and efficacy in the FUL and LET cohorts. Results: At data cutoff, 64 and 36 pts were enrolled in the FUL and LET cohorts, respectively; 39 pts ( FUL, n = 21; LET, n = 18) have safety and efficacy data with ≥6 mo follow-up and are reported here. Data on 100 pts enrolled at the time of data cutoff will be presented. In the 39 pts with ≥6 mo follow-up, median ALP duration was 5.3 and 5.5 mo in FUL and LET, respectively; median duration of FUL and LET was 5.6 mo. Median relative ALP dose intensity was 93% ( FUL) and 87% ( LET). Most common grade ≥3 adverse events were hyperglycemia (38.1% ( FUL) and 27.8% ( LET)) and rash (4.8% ( FUL) and 27.8% ( LET)). Only 2 pts (5%; 1 pt per cohort) discontinued due to an AE. In pts with centrally confirmed PIK3CA mutation (n = 20 ( FUL); n = 17 ( LET)), ORR was 20% ( FUL) and 18% ( LET), CBR was 40% ( FUL) and 35% ( LET). Efficacy and safety data for the 100 enrolled pts will be presented at the meeting. Conclusions: Pending further readout of the ongoing BYLieve trial, safety and tolerability of ALP and hormonal therapy in pts with prior CDKi are consistent with those of SOLAR-1; discontinuation due to toxicity was rare. NCT03056755. Clinical trial information: NCT02437318.

Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Three-year follow-up.

7500 Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor. This Phase 1b/2 trial evaluated acalabrutinib with the CD20 antibody Ob in TN and R/R CLL. Methods: Patient (pts) with TN and R/R (≥1 prior therapy) CLL were eligible. In 28-day cycles, acalabrutinib was given at 100 mg BID or 200 mg QD PO (n=15; all switched to 100 mg BID) until progressive disease (PD); Ob was given in standard fashion for 6 cycles starting with Cycle 2. The primary endpoints were overall response rate (ORR) and safety. Minimal residual disease (MRD) was assessed using flow cytometry (sensitivity 10-4). Results: 19 TN and 26 R/R pts were treated; median age of all pts was 61 y (range 42-76). Pt characteristics, disposition, efficacy and MRD are in the Table. Common adverse events (AEs; any grade) were upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%) and dizziness (47%). Common Gr 3/4 AEs were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight and cellulitis (9% each). There were 2 (4%) Gr 3 bleeding events (hematuria, muscle hemorrhage) and 1 (2%) Gr 3 atrial fibrillation event. Conclusions: Acalabrutinib plus Ob was well tolerated and yielded high response rates that were durable and deepened over time in TN and R/R CLL patients. Clinical trial information: NCT02296918. [Table: see text]

Derazantinib (DZB) provides antitumor efficacy regardless of line of therapy in patients (pts) with FGFR2-fusion positive advanced intrahepatic cholangiocarcinoma (iCCA).

e15607 Background: FGFR2 fusions are prevalent in 13-22% of iCCA and known oncogenic drivers. DZB is a kinase inhibitor with potent pan-FGFR activity. In a non-comparative Phase 2a study, DZB was administered to 29 pts with FGFR2-fusion positive advanced, inoperable iCCA, either as first-line (1L) (n = 2), 2L (n = 13), 3L (n = 10), 4L (n = 2) or 5L therapy (n = 2). The objective response rate (ORR) with DZB was 21%, disease-control rate (DCR) 83% and median PFS 5.7 months (Mazzaferro et al. 2018 BJC). Data from biliary tract cancer studies suggest decreasing treatment effects of chemotherapy with increasing lines of treatment. Here, we present a post-hoc analysis of outcomes of pts treated with DZB in 1L/2L (n = 15) compared to pts treated post-2L (n = 14). Methods: Pts received 300 mg DZB QD PO. Eligibility criteria included locally confirmed, positive testing of FGFR2 fusion expression (FISH or NGS), ECOG PS 0-1. Objective responses were determined using RECIST 1.1. Disease control rate was defined as CR, PR or SD. Results: The mean age of pts treated in 1L/2L was 66y and 55y in post-2L; 73% were females in 1L/2L and 50% in post-2L treatment; other demographic variables were balanced between groups (87% vs 86% of liver target lesions, median baseline lesion size of 97.5 mm vs 109.5 mm, ECOG PS0 was 60% vs 71%). Of 15 1L/2L group pts, 12 (80%) had prior platinum-based chemotherapy as compared to all 14 pts in the post-2L group. In the 1L/2L and post-2L groups, ORR was 20% and 21%, DCR was 80% and 86%, and a reduction in sum of the largest diameter of target lesions was observed in 60% and 64% of pts, respectively. Median PFS was 5.5 mo (95% CI, 1.9-11.9) and 6.2 mo (3.6-9.2) for the 1L/2L and post-2L groups, respectively. Types of drug-related adverse events were similar in 1L/2L and post-2L. Conclusions: Anti-tumor efficacy of DZB in iCCA patients measured either by ORR, DCR, tumor shrinkage or PFS was numerically similar irrespective of treatment line. These data suggest that DZB is an effective treatment option that can be applied early in the treatment continuum of iCCA patients or at later stages to offer anti-tumor efficacy and disease control. Clinical trial information: 01752920.

CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study.

549 Background: Glutaminase (GLS) is a key enzyme that controls glutamine utilization, a metabolic pathway upregulated in RCC and important for tumor proliferation and survival. CB-839 is a first-in-clinic, small molecule, reversible, oral GLS inhibitor that synergizes with cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, in preclinical RCC models to inhibit metabolic pathways and enhance anti-tumor activity. Cabo monotherapy is associated with a 17% overall response rate (ORR) for clear cell (cc) mRCC (Choueiri et al. Lancet Oncol. 2016). Here we present findings from a Phase 1 study cohort evaluating the safety, efficacy, and recommended Phase 2 dose (RP2D) of CB-839 + Cabo in patients (pts) with mRCC as 2L+ therapy. Methods: Eligible pts had mRCC with cc or papillary histology, ECOG 0-1, RECIST measurable disease, and, for cc pts, treatment with ≥1 prior anti-VEGF therapy. Escalating doses of CB-839 (600-800 mg PO BID) plus Cabo (60 mg PO QD) were evaluated using a 3+3 design. Tumor response was assessed per RECIST 1.1 every 8 wks. Results: The CB-Cabo cohort enrolled 13 pts with a median 3 (range, 0-7) prior lines of therapy. No maximum tolerated dose was reached; 800 mg was selected as the CB-839 RP2D. The most common treatment-related AEs (occurring in >25% of pts) were diarrhea (62%), decreased appetite (46%), ALT increased (39%), fatigue (39%), AST increased (31%), nausea (31%), and rash (31%); Gr ≥3 treatment-related AEs included diarrhea, hypertension, platelet count decreased, and hallucination (n=1 each). Among 12 evaluable pts, ORR was 42% and disease control rate (DCR = complete response + partial response [PR] + stable disease [SD]) was 100%: 42% (5/12) PR, 58% (7/12) SD. Among 10 evaluable cc mRCC pts, 50% (5/10) had PRs, 50% (5/10) SDs. As of Sept 24, 2018, 5 pts received >12 months treatment; 4 remain on study. Conclusions: CB-839 plus Cabo showed encouraging clinical activity and tolerability in heavily pretreated mRCC pts, with response rates for cc mRCC (50% ORR, 100% DCR) comparing favorably to historical Cabo monotherapy. A randomized Phase 2 study of CB-839 + Cabo vs. Cabo + placebo in cc mRCC is ongoing. (CANTATA; NCT0342821) Clinical trial information: NCT02071862.

ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer.

259 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often relatively short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC degrader, ARV-110, that promotes ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, and DMPK, toxicology and preclinical efficacy studies. Results: ARV-110 robustly degrades AR in all cell lines tested, with an observed half-maximal degradation concentration (DC50) of ~1 nM. ARV-110 treatment leads to highly selective AR degradation, as demonstrated by proteomic studies. In VCaP cells, PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces apoptosis at low nanomolar concentrations. Further, ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling has been achieved in LNCaP, VCaP and prostate cancer patient derived xenograft (PDX) models. Notably, ARV-110 demonstrates in vivo efficacy and reduction of AR-target gene expression in a long term, castrate, enzalutamide-resistant VCaP tumor model. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader, ARV-110, that demonstrates efficacy in multiple prostate cancer models. ARV-110 has completed IND-enabling studies and FIH studies are planned for 1Q2019.

Ibrutinib Dose Reduction Does Not Affect Progression-Free Survival in Patients with Waldenstrom Macroglobulinemia

Introduction: Ibrutinib is an oral Bruton Tyrosine Kinase inhibitor, approved for the treatment of symptomatic Waldenstrom Macroglobulinemia (WM). MYD88 and CXCR4 mutations affect progression-free survival (PFS) in patients with WM. In some cases, ibrutinib dose reductions are needed for the management of toxicity. However, it remains unclear if ibrutinib dose reductions adversely affect PFS in WM patients.Methods: We evaluated 217 consecutive patients with the clinicopathological diagnosis of WM who were symptomatic and received treatment with ibrutinib. We analyzed relevant clinical features and their association with the risk of dose reduction, using logistic regression models, as well as PFS using Cox proportional-hazard regression models. Time to events was estimated using the Kaplan-Meier method. p<0.05 were considered statistically significant.Results: All 217 patients were initiated on ibrutinib monotherapy at the approved dose of 420 mg by mouth (PO) once daily (QD). At a median follow-up of 26 months (95% CI 22-31 months), 159 patients (73%) continued ibrutinib without dose-reduction, while 58 (27%) patients had a decrease in their ibrutinib dose. There was no difference in follow-up between those with and without dose reduction. Of the 58 patients that dose reduced, 45 (78%) were reduced to 280 mg daily; 12 patients (21%) were reduced to 140 mg daily, and 1 (2%) to 140 mg every other day.The median time to ibrutinib dose reduction from 420 mg PO QD to 280 mg PO QD was 155 days (95% CI 89-282 days), and median time to dose reduction from 280 mg PO QD to 140 mg PO QD was 55 days (95% CI 24-260 days). Reasons for ibrutinib dose reduction included cytopenia(s) (n=13; 24%), arrhythmia (n=9; 17%), musculoskeletal discomfort (n=8; 15%), constitutional symptoms (n=6; 11%), skin changes/rash (n=5; 9%), mouth sores (n=4; 7%), gastrointestinal symptoms (n=3; 6%), infections (n=3; 6%), bleeding (n=2; 4%) and transaminase elevation (n=1; 2%). Patients in whom ibrutinib dose reduction was needed were more likely to be older than 65 years (76% vs. 47%; p<0.001), had higher International Prognostic Scoring System for WM (IPSSWM) at ibrutinib initiation (IPSSWM 1, 2 and 3 were 19%, 23% and 58% vs. 24%, 39% and 37%, respectively; p=0.03), and were more likely to have attained a major response (93% v. 69%; p<0.001) than patients in whom ibrutinib dose was not reduced.There were no differences in baseline characteristics including sex, hemoglobin levels, platelet counts, beta-2-microglobulin levels, serum IgM levels, bone marrow involvement, previous treatment, MYD88 and CXCR4 mutational status and time from WM diagnosis to ibrutinib initiation between those with and without dose reduction. Regression analyses showed higher odds of dose reduction occurring in patients >65 years (OR 3.6, 95% CI 1.8-7.1; p<0.001) and those who had attained a major response (OR 6.0, 95% CI 2.1-17.5; p=0.001). The median PFS for the entire group was not reached, and the 3-year PFS rate was 76% (95% CI 68-83%). Factors associated with a worse PFS were platelet count <100 K/uL (HR 3.9, 95% CI 1.8-8.7; p=0.001) and CXCR4 mutations (HR 3.0, 95% CI 1.5-6.0; p=0.001). Expression of mutated MYD88 (HR 0.01, 95% CI 0.00-0.09; p<0.001) and attainment of major response (HR 0.23, 95% CI 0.12-0.43; p<0.001) were associated with a better PFS. Importantly, those who experienced a reduction in their ibrutinib dose showed no significant difference in PFS (HR 1.19, 95% CI 0.61-2.35; p=0.61; Figure 1A). There were no differences between patients who reduced to 280 mg PO QD (HR 1.0, 95% CI 0.5-2.2; p=0.99) or 140 mg PO QD (HR 1.9, 95% CI 0.7-5.5; p=0.22) versus those without dose reduction (Figure 1B).Conclusion: Ibrutinib dose reduction occurred in 27% of patients with WM, at a median time to dose reduction of 155 days. Patients older than 65 years and those with major responses were more likely to have a dose reduction. With a median follow-up time of 26 months, ibrutinib dose reduction did not significantly impact PFS. [Display omitted] DisclosuresCastillo:Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Genentech: Consultancy. Hunter:Pharmacyclics: Consultancy. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding.

A Phase 2 Study of Cpi-0610, a Bromodomain and Extraterminal (BET) Inhibitor, in Patients with Myelofibrosis (MF)

MF is a myeloproliferative neoplasm characterized by abnormal megakaryocytes and elevated proinflammatory cytokines which results in bone marrow fibrosis, progressive hepatosplenomegaly due to extramedullary hematopoiesis, and debilitating constitutional symptoms. Current treatments, including ruxolitinib (the only approved drug for MF), provide symptomatic relief but have limited effects on the underlying disease. Effective therapies with potential MF disease course modification and second line therapies are urgently needed.CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Although CPI-0610 was tested at doses as high as 400 mg PO QD, the maximum tolerated dose was 225 mg PO QD for 2 weeks on, 1 week off. Clear anti-tumor activity was observed in patients with lymphomas, particularly ABC-DLBCL (Blum et al. TAT conference 2018). Preclinical data on CPI-0610 demonstrated downregulation of pro-inflammatory cytokines through its effects on NF-κB pathway as well as inhibition of megakaryocyte differentiation. Both of these features are thought to be important in the pathogenesis of MF. In addition, a recent preclinical publication using a mouse model of MF, suggests that BET inhibition reduces inflammatory cytokine production, platelet counts, spleen volume and bone marrow fibrosis, the effects of which were further magnified when combined with ruxolitinib (Kleppe et al. 2018). Taken together, these data suggest that BET inhibitors such as CPI-0610, administered with and without ruxolitinib, have the potential to affect the underlying MF disease and supports further clinical evaluation of CPI-0610 in patients with MF. Therefore, we have embarked on a Phase 2 trial of CPI-0610 as monotherapy or in combination with ruxolitinib.This Phase 2 study aims to evaluate CPI-0610 as a monotherapy and in combination with ruxolitinib in patients with MF who are not eligible to receive a JAK inhibitor or have had an inadequate response to ruxolitinib. The primary objectives are to evaluate spleen volume response by imaging after 24 weeks of therapy and to evaluate the effect on transfusion independence rate. Other key secondary objectives are to evaluate the change in patient reported outcomes and the duration of splenic response. Exploratory objectives include characterizing the effects of treatment on the bone marrow and blood biomarkers. The Phase 2 study has a 2-stage design to enroll up to 35 patients in each arm (monotherapy and combination therapy) if ≥2 responses are observed during stage 1. The study is registered at ClinicalTrials.gov NCT02158858. DisclosuresKremyanskaya:Incyte: Research Funding. Hoffman:Formation Biologics: Research Funding; Summer Road: Research Funding; Incyte: Research Funding; Merus: Research Funding; Janssen: Research Funding. Mascarenhas:CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Merck: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Mertz:Constellation Pharma: Employment. Garner:Constellation Pharma: Employment. Senderowicz:Constellation Pharma: Employment.

MA15.02 Long-Term Safety and Clinical Activity Results from a Phase Ib Study of Erlotinib Plus Atezolizumab in Advanced NSCLC

Patients with EGFR mutation–positive non-small cell lung cancer (NSCLC) achieve favorable outcomes with EGFR tyrosine kinase inhibitors (TKIs); however, the long-term efficacy of these agents is limited by development of acquired resistance. Atezolizumab (anti–PD-L1 mAb) monotherapy has shown tolerability and durable clinical activity in NSCLC. By selectively targeting PD-L1 to block its interaction with receptors PD-1 and B7.1, atezolizumab can reinvigorate anti-cancer T-cell activity. Thus, combining atezolizumab and erlotinib could result in improved anti-tumor immunity and durable anti-tumor effects. Safety and preliminary clinical activity from a Phase Ib study of erlotinib plus atezolizumab in locally advanced or metastatic NSCLC have been previously reported (Rudin, et al. WCLC 2016). Here we describe updated findings from this study (NCT02013219). EGFR TKI-naive patients with NSCLC were enrolled into a safety-evaluation stage (Stage 1) regardless of EGFR status, and an expansion stage (Stage 2) enrolled patients with EGFR-mutant NSCLC who were previously untreated or treated with 1 prior non–EGFR TKI therapy. A 7-day run-in period with erlotinib 150 mg PO QD was followed by addition of atezolizumab 1200 mg IV q3w. The primary endpoint was safety/tolerability of the combination; secondary endpoints included clinical activity per RECIST v1.1. At data cutoff (August 18, 2017), 28 patients (Stage 1, n = 8; Stage 2, n = 20) were evaluable for safety, and the median survival follow-up was 26.0 months (range, 7.8-32.9; Stage 2). The median age was 61 years (range, 47-84), and the most common EGFR mutation was exon 19 deletion (44%). Grade 3 treatment-related AEs (TRAEs) were reported in 43% of patients; no Grade 4 or 5 TRAEs occurred. The most common TRAEs were increased ALT, pyrexia, rash and diarrhea (2 patients each). Serious AEs occurred in 54% of patients; treatment-emergent AEs led to atezolizumab discontinuation in 18% and erlotinib discontinuation in 11%. Clinical activity was evaluated in Stage 2 patients. ORR was 75% (95% CI: 50.9, 91.3), with a median DOR of 16.7 months (range, 4.2-26.0+). Median PFS was 15.4 months (95% CI: 8.4, not estimable [NE]), and median OS was 32.7 months (95% CI: 32.7, NE). Atezolizumab plus erlotinib demonstrated a tolerable safety profile and compared favorably with prior reports of efficacy with erlotinib monotherapy. OS data are expected to mature and improve with longer follow-up; updated clinical and biomarker data will be presented. Further investigation of the combination is warranted to assess its full potential.

P1.12-04 A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients

Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy. Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability. Section not applicable Section not applicable

Abstract LB-087: Inflammatory and stem-like colorectal cancer (CRC) subtypes identified in patient-derived xenograft (PDX) models show tumor growth inhibition (TGI) by the combination of trametinib (T) and neratinib (N) irrespective of KRAS mutation (MT) status

Abstract Background: KRAS MT CRC tumors demonstrate constitutively activated RAF-MEK-ERK signaling pathways and resistance to anti-EGFR therapies. In preclinical studies using KRAS MT CRC cell lines, resistance to MEK inhibitors (MEKi) led to induction of ERBB3. Using kinome-centered synthetic lethality screen, suppression of ERBB3 receptor tyrosine kinase is strongly synergistic with MEKi in CRC cell lines. We previously showed that KRAS MT cell lines of intrinsic inflammatory subtype were sensitive to MEKi and N, but stem-like subtype cell lines were resistant regardless of KRAS MT status. In this study, we evaluated treatment with T + N in 5 PDX models (Champions Oncology). PDX models were characterized by genomic signature for intrinsic subtypes, and molecularly profiled for KRAS, BRAF, PI3K, NRAS, and MSI status. Methods: An initial study was performed for dose tolerability. Efficacy studies were undertaken with 10 mice in each of 4 cohorts: vehicle, N 40 mg/kg po qd , T 1.0 mg/kg po qd, and N 40 mg/kg + T 1.0 mg/kg. Doses were given until the model reached endpoint. Mean tumor volumes (MTV) of treatment groups were compared to control group to determine % tumor growth inhibition (TGI). Tissue specimens were obtained from vehicle and all treatment arms for WES, RNA seq, and phosphoprotein analysis. Results: Model NoSubtypeMT profile% TGI (T,N, T+N)*p-value v controlCTG-0117InflammatoryKRAS WT/MSS43% v 49% v 76%0.215 v 0.17 v 0.009CTG-0382InflammatoryKRAS MT/MSS62% v 40% v 80%0.009 v 0.11 v 0.001CTG-0406InflammatoryKRAS MT/MSS43% v 46% v 67%0.001 v 0.0006 v 0.0001CTG-0069Stem-likeKRAS MT/MSS39% v 32% v 61%0.12 v 0.31 v 0.015CTG-0079Stem-likeKRAS MT/MSS10% v 22% v 42%0.91 v 0.51 v 0.068 *TGI was determined by calculating % TGI (100% x [1-(final MTV − initial MTV of a treated group) / (final MTV – initial MTV of the control group)]). Conclusions: T + N was well tolerated as evaluated by body weight and demonstrated TGI in all 3 inflammatory models and in 1 of two stem-like CRC PDX models. Importantly, these tumors were KRAS MT and MSS suggesting that T + N may be a promising targeted therapy for related CRC pts. WES, RNA seq, and phosphoprotein analyses from vehicle and treatment arms will be performed. This analysis may define potential biomarkers related to sensitivity or resistance to T + N and inform additional targeted therapies. Support: Champions Oncology; Puma Biotechnology Citation Format: Rekha Pal, Nan Song, Ying Wang, Ashok Srinivasan, Peter C. Lucas, Carmen J. Allegra, Angela M. Davies, Alshad S. Lalani, Samuel A. Jacobs, Katherine L. Pogue-Geile. Inflammatory and stem-like colorectal cancer (CRC) subtypes identified in patient-derived xenograft (PDX) models show tumor growth inhibition (TGI) by the combination of trametinib (T) and neratinib (N) irrespective of KRAS mutation (MT) status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-087.

Abstract CT161: Clinical study of PD-1 inhibitor with mTOR inhibitor for relapsed and refractory brain tumors

Abstract In this phase I/II study the combination regimen is used to treat recurrent or refractory malignant glioma patients. The inclusion criteria: 1) Histologically confirmed WHO IV. Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma. 2) Patients must be at first or second relapse following initial radiation-chemotherapy therapy. 3) Must provide tumor tissue. 4) Molecular diagnosis includes the mutation of PIK3CA, KRAS, TSC1 and PTEN expression decreased, meet the above 2 and above. High expression of PD-L1 in tumor and tumor infiltrating lymphocytes consider as drug specifically targeting T-cell checkpoint pathways. 5) KPS&amp;gt;/= 60. 6) Measurable contrast-enhancing tumor consists of a miaxmal volume of 3*3 cm. 7) Stable doses of steroids for 5 days, no more than 2 mg dexamethasone total per day. 8) Absolute neutrophil count (ANC) &amp;gt;/=1,500 /mcL; platelets &amp;gt;/=100,000/mcL; hemoglobin &amp;gt;/= 9 g/dL; serum creatinine /= 60 mL/min for subject with creatinine levels &amp;gt; 1.5 × institutional ULN. 9) Both sexual and age &amp;gt;/= 18 years on day of signing informed consent, 5 to 18 years of age signing informed consent by parents. Exclusion criteria: 1) Treated previously with bevacizumab. 2) Has tumor localized primarily to the brainstem or spinal cord. 3) Has received prior interstitial brachytherapy, implanted chemotherapy, or CAR-T cell therapy. 4) Currently participating in or has participated in a study of an investigational agent or using an investigational device 4 weeks since last dose of agent administration. 5) Has a diagnosis of immunodeficiency or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial. 6) Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 7) Has an active infection requiring systemic therapy. 8) Pregnant or breastfeeding. 9) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 antibody. 10) History of HIV, HBV, HCV. 11) Has received a live vaccine within 30 days prior to the first dose of trial treatment. According to the results of tumor molecular evaluation, patients would be divided into three intervention groups. The interventions are EVE group (Everolimus 10mg PO QD), PD-1 inhibitor monotherapy group (PD-1 inhibitor 2mg/kg ivgtt Q3W) and combination group (Everolimus 10mg PO QD + PD-1 inhibitor 2mg/kg ivgtt Q3W). Primary outcome measure: 6 month progression-free survival rate, progression will be determined by review of MRI exams every month, assessed using iRANO criteria. Secondary outcome measures: 1) Overall survival (OS) and progression-free survival (PFS). 2) Incidence of grade 3+ toxicities. 3) Helper and effecter T cells active percent, T reg and MDSC percent in peripheral blood will be detected before and after treatment Day 1, 3, 7 and 3 weeks in every cycle. This clinical trial has supported by IRB of Renji hospital and registered on ICTRP identifier: ChiCTR-OON-16008330. Citation Format: zhihua Chen, Yongming Qiu. Clinical study of PD-1 inhibitor with mTOR inhibitor for relapsed and refractory brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT161.

Abstract 4719: Small-molecule antagonists of the Aryl Hydrocarbon Receptor (AhR) promote activation of human PBMCs in vitro and demonstrate significant impact on tumor growth and immune modulation in vivo

Abstract Cancer cells utilize a variety of pathways to generate an immune permissive growth environment and evade the host anti-tumor immune response. One such pathway is production of T-cell inhibitory tryptophan (Trp) metabolites, kynurenine and kynurenic acid (KYN), via up-regulation of indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO2) and up-regulation of the KYN- receptor (aryl hydrocarbon receptor, AhR) in infiltrating lymphoid and myeloid cells. Through AhR activation, KYN both directly and indirectly, via stimulation of regulatory T-cells (Tregs), dendritic cells (DCs) and tumor-associated macrophages (TAM), modulates CD8+ and CD4+ T-cell function resulting in potent inhibition of anti-tumor immunity. Inhibition of AhR activation therefore represents a novel approach to blocking the immuno-inhibitory effects of Trp metabolites generated by endogenous IDO1 and TDO2. To thwart the effects of KYN and other immunosuppressive AhR agonist ligands, we have generated a series of small-molecule antagonists of the human and mouse AhR. To further analyze the effects of AhR inhibition on immuno-modulation and tumor growth, we selected from our series a highly potent antagonist of AhR (IDB-AHRi). In an XRE-dependent luciferase reporter system, IDB-AHRi blocked activation of AhR by 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) with an IC50 of 111 and 3 nM in human HEPG2 and mouse HEPA1C1C7 cell lines respectively. IDB-AHRi inhibited translocation of cytoplasmic AhR to the nucleus and protected AhR from TCDD-induced degradation. When human peripheral blood mononuclear cells were treated with IDB-AHRi ex-vivo, expression of IFN-γ and TNF-α was significantly enhanced, an effect that could be reversed with the addition of TCDD. In vivo, IDB-AHRi dosed at 30 mg/kg (PO QD) in the CT26 colon carcinoma syngeneic mouse model resulted in a reduction of tumor growth, an increase in tumor-infiltrated CD45+CD8+Ki67high T-cells and a significant reduction in the frequency of tumor infiltrated FoxP3+CD4+ regulatory T-cells and tumor associated M2-like macrophages. In summary, this data demonstrates that blocking AhR with a highly potent antagonist can significantly enhance T-cell activity in vitro and drive anti-tumor immunity in vivo, resulting in reduced tumor growth. Citation Format: James Joseph, Marcos Gonzalez-Lopez, Christina Galang, Candy Garcia, Hadia Lemar, Jing Lu, Kedar Vaidya, Marcus Fischer, Christian Frey, Muzaffar Alam, Bing Yao, Michael Dillon, Jeffrey H. Hager, Eleni Venetsanakos, Fred Aswad. Small-molecule antagonists of the Aryl Hydrocarbon Receptor (AhR) promote activation of human PBMCs in vitro and demonstrate significant impact on tumor growth and immune modulation in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4719.

Abstract 2197: Surface marker and gene expression profiling of tumors from PDX models of small cell lung cancer with varying sensitivity to growth inhibition by the p70S6K/AKT1/3 inhibitor M2698

Abstract Small Cell Lung Cancer (SCLC) is characterized by rapid tumor growth and currently, there are few therapeutic options. As part of the development of M2698, a potent, selective inhibitor of p70S6K and AKT 1/3, the compound was tested in a preclinical screen of 45 patient derived xenograft (PDX) models of SCLC. In this screen, two mice were implanted subcutaneously with tumors for each model; one mouse was treated with vehicle while the other was treated with M2698 25 mg/kg QD po and tumors were measured 2x/week until the tumor in the vehicle-treated mouse reached ~1200 mm3. Tumor control (tumor stasis or regression) was seen in 12 (27%) of the models. From these data, a subset of models that were the most and the least sensitive to M2698 (n=7) were selected for implantation into a new set of mice. Tumors were profiled once they reached ~800 mm3 for tumor cell surface markers potentially correlating with sensitivity to M2698 seen in the previous study. PDX model systems are capable of recapitulating the intra-tumor heterogeneity (ITH) observed in the original patient tumor. The relationship between ITH and drug response/acquired drug resistance has been clearly demonstrated. Thus, a more detailed examination of this complexity in PDX tissue enables one to elucidate the underlying mechanisms in a reproducible, biologically relevant system. We have previously shown that cell surface marker profiles of PDX derived tumor tissue demonstrate high intra-model reproducibility whereas each model has a unique profile. In addition, some markers have a distinct heterogeneity. Gene expression profiling of tumor cell subpopulations identified by some of these specific markers suggest different biological roles for these subpopulations with relevance to their drug responses. Here we show surface marker and gene expression profiles of multiple PDX models for SCLC. We have evaluated 50+ markers commonly used to identify tumor initiating cells (e.g. CD44, CD90, CD133, CD166, CD184), EMT or aggressiveness (e.g. CD166, EphB2, CD324, CD325) or drug targets (e.g. CD184, EGFR, Her2) to establish extensive marker profiles. Our data reveal that surface marker profiles in SCLC PDX models are consistent among tumors from mice bearing the same model, show major differences from other PDX (e.g. breast) cancer types and heterogeneity exists for several markers of interest. By correlating gene expression and surface marker profiles in the current preclinical study, we aim to illuminate the interactions of major cell subpopulations within SCLC PDX tumor tissue and also investigate potential markers of sensitivity to growth inhibition by treatment with M2698. Overall, our workflow of deep phenotyping may provide tools for sample characterization, quality control and possibly study of cellular response to varying selective pressures such as drug challenges. Citation Format: Friedrich Hahn, Warren Porter, Eileen Snowden, Mitchell Ferguson, Frances Tong, William S. Dillmore, Anderson Clark, Hong Zhang, Rainer Blaesius. Surface marker and gene expression profiling of tumors from PDX models of small cell lung cancer with varying sensitivity to growth inhibition by the p70S6K/AKT1/3 inhibitor M2698 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2197.

Abstract 5236: ARV-110: An androgen receptor PROTAC degrader for prostate cancer

Abstract The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Here we report an orally bioavailable small molecule ARV-110 that leads to ubiquitination and degradation of AR. ARV-110 completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) &amp;lt; 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target genes PSA and FKBP5, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, ARV-110 demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. In summary, we report preclinical data on ARV-110, an orally bioavailable androgen receptor PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer. Citation Format: Taavi Neklesa, Lawrence B. Snyder, Ryan R. Willard, Nicholas Vitale, Kanak Raina, Jennifer Pizzano, Deborah Gordon, Mark Bookbinder, Jennifer Macaluso, Hanqing Dong, Zheng Liu, Caterina Ferraro, Gan Wang, Jing Wang, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. ARV-110: An androgen receptor PROTAC degrader for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5236.

Patient-reported outcomes (PROs) in IMmotion151: Atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun) in treatment (tx) naive metastatic renal cell carcinoma (mRCC).

4511Background: The randomized, open-label Phase III IMmotion151 study met its coprimary endpoint in PD-L1+ patients (pts) with improvement in investigator-assessed PFS for atezo + bev vs sun (HR 0.74; median 11.2 vs 7.7 mo, P = 0.02). Encouraging efficacy was also observed in the intent-to-treat (ITT) population (HR 0.83; 11.2 vs 8.4 mo) (Motzer, ASCO-GU 2018). PROs were evaluated as secondary and exploratory endpoints to document pt perspective on overall clinical benefit for each tx. Methods: Pts received atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w (n = 454) or sun 50 mg PO QD 4 wk on/2 wk off (n = 461). Pts completed the MD Anderson Symptom Inventory (MDASI) and Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (FKSI-19) questionnaires on days 1 and 22 of each 6 wk cycle, at end of tx, and during survival follow-up. Prespecified concepts included symptom burden (MDASI symptom severity and symptom interference with daily living) and bother from tx side effects (FKSI-19 GP5 item). Health-re...

Phase I/II trial of pembrolizumab(P) and vorinostat(V) in recurrent metastatic head and neck squamous cell carcinomas (HN) and salivary gland cancer (SGC).

6025 Background: Epigenetic modification is increasingly recognized as a mechanism for tumor immune evasion. This clinical trial explored the activity of P with the HDAC inhibitor V in HN and SGC. Methods: Patients(pts) with progressing incurable HN and SGC with ECOG ≤1, no prior immunotherapy, RECIST 1.1 measurable disease, and normal organ function were eligible. Controlled brain metastases were permitted. PDL1 expression was not an eligibility criterion. P 200mg was given IV q21 days (d) , with V 400mg QD PO, 5d on and 2d off, both started on d1 of each cycle. The primary endpoint was safety according to CTCAE v. 4.03. Secondary endpoints were RECIST 1.1 objective response rates and biomarker collection. Results: From 11/2015 to 8/2017, 25 HN and 25 SGC pts were enrolled. Among all 50 pts, median age was 61 (range 33-86) yrs, 39 (78%) were male, 21(62%) were never smokers, 27 (54%) had ECOG 0. In HN, primary sites were oropharynx 17 (68%), nasopharynx 4 (16%), oral cavity 1(4%), skin 2 (8%) and unknown 1 (4%). Thirteen(52%) were p16+ oropharynx HN. SGC histologies were adenoid cystic (ACC) 12(48%), acinic cell (AciC) 3(12%), mucoepidermoid 3(12%), ca ex. pl. adenoma 2(8%). There was 1(4%) pt each with adenocarcinoma, salivary duct, epithelial-myoepithelial, clear cell, parotid lymphoepithelioma-like(LEL-C) carcinoma. The median (range) treatment cycles received in HN was 6 (1-33), and SGC 9 (1-34). Adverse events regardless of cause (AEs) in all pts were: 27 (54%) Grade ≥1, 18(36%) Grade≥ 3. Nine(18%) pts required V dose reductions. The most common AEs in all pts were renal insufficiency in 7(14%), fatigue 6 (12%) and nausea 3 (6%). There were 3 (12%) deaths on study, 1 aspiration pneumonia, 1 myocardial infarction, and 1 presumed pneumonitis from P. Responses in HN were: complete response (CR) 0, partial response(PR) 8 (36%), stable disease(SD) 5 (20%). Efficacy in SGC:CR 0, PR 4 (16%) in 1 LEL-C, 2 AciC and 1 ACC, SD 14(56%). With a median follow up of 8.7 mos for all pts, in HN median PFS was 4.5 mos, median OS, 12.6 mos; in SGC median PFS was 7 mos, and median OS 13 mos. Conclusions: P+V demonstrated activity in HN, with fewer responses in SGC. Serum and tissue biomarker analyses are ongoing. Clinical trial information: NCT02538510.

Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus (E) or cabozantinib (Cabo) in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell cancer (mRCC).

603 Background: CB-839 is a first-in-class inhibitor of GLS that targets tumor glutamine utilization, a pathway upregulated in kidney cancer. CB-839 combines with E or Cabo in pre-clinical RCC models to inhibit metabolic pathways resulting in enhanced anti-tumor activity. The CX-839-001 study includes cohorts evaluating the safety, efficacy and recommended Phase 2 dose (RP2D) of CB-839 in combination with E (CBE) or Cabo (CB-Cabo) in pts with mRCC. Here we report results from the CBE and CB-Cabo cohorts. Methods: Eligibility criteria included mRCC with cc or pap histology, ECOG 0-1, RECIST measurable disease and, for cc pts, treatment with at least 1 prior anti-VEGF therapy. Pts received escalating doses of CB-839 (PO BID) in a 3+3 design, either 400-800 mg with E (10 mg PO QD) or 600-800 mg with Cabo (60 mg PO QD). Tumor response (RECIST 1.1) was assessed every 8 wks. Results: 27 pts (22 cc, 3 pap, 2 other) were enrolled in CB-E escalation (n = 17) and expansion (n = 10) cohorts (7 at 400 mg, 13 at 600 mg, 7 at 800 mg) and 11 pts (9 cc, 2 pap) in CB-Cabo escalation cohorts (6 at 600 mg, 5 at 800 mg). Median prior lines of therapy was 2 for CBE (including 64% of cc pts with ≥2 prior anti-VEGF therapies) and 3 for CB-Cabo (range 0-6). A maximum tolerated dose was not reached; 800 mg was selected as the RP2D for CB-839. The most common treatment-related Gr≥3 AEs were fatigue (11%), anemia, hyperglycemia, and neutropenia (7% each) for CBE (N = 27) and diarrhea (14%) and platelet count decreased (14% including 1 DLT at 600 mg) for CB-Cabo (N = 7). Of 24 evaluable CBE pts there was 1 PR and 21 SD for a disease control rate (DCR = CR + PR + SD) of 92% with a median PFS of 7.1 mo (95% CI 4 - 11). For 9 evaluable CB-Cabo pts the ORR and DCR were 44% (4 PR) and 100%, respectively. Conclusions: The tumor metabolism inhibitor CB-839 combines with full dose of RCC targeted therapies, E and Cabo, with good tolerability and encouraging clinical activity in heavily-pretreated mRCC pts. CB-Cabo ORR and DCR of 44% and 100% are promising, and CBE DCR of 92% and PFS of 7.1 mo compare favorably to historical E monotherapy. Randomized Phase 2 studies have been initiated (CBE) or are planned (CB-Cabo). Clinical trial information: NCT02071862.

Niclosamide in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC): initial results from a phase Ib/II trial.

192 Background: Prostate cancer is driven by androgen receptor (AR) signaling. The variant AR-V7 lacks the ligand binding domain, constitutively activates the AR pathway, and confers resistance to Abiraterone (Abi) and enzalutamide (Enza). We discovered that the anti-helminthic drug niclosamide targets AR-V7 and sensitizes resistant CRPC to Enza and Abi. We hypothesize that niclosamide/PDMX1001 potentiates the efficacy of Abi against CRPC. Here we report the initial results of this ongoing investigator-initiated phase Ib/II trial. Methods: Eligible patients (pts) have progressive CRPC with serum testosterone &lt; 50 ng/dl. No prior Abi was allowed. In the Phase Ib cohort, pts received Abi 1000 mg PO qd, prednisone 5 mg PO bid, with intrapatient dose-escalation of niclosamide/PDMX1001 from 400 mg PO bid to 1600 mg PO tid. Trough niclosamide/PDMX1001 levels were measured. The Phase II cohort will enroll 27 patients with detectable AR-V7 in the peripheral blood. Co-primary endpoints include toxicity and response as determined by the Prostate Cancer Working Group 2 criteria. Results: Of 6 pts (age 74-83) in the Phase Ib cohort, five pts tolerated a niclosamide/PDMX1001 dose of 1,600 mg po tid without dose limiting toxicity; per protocol, this is the recommended Phase II dose. Niclosamide/PDMX1001 trough level was 0.305 and 0.496 µM in the two pts analyzed thus far, higher than the target level of 0.1µM required for anti-cancer activity. Of 6 pts, two pts achieved complete PSA response ( &lt; 0.01 ng/ml), compared to historical control 0/30 pts treated with Abi alone; two with partial PSA response (≥50% decrease). Of the remaining two pts, one was prematurely taken off from the study after one cycle because of rising PSA, and the other had PSA decrease of 17.1%, but biopsy of the only enlarged lymph node showed all necrotic tissue. The only toxicity was Grade 1 nausea and diarrhea. The Phase II cohort will now enroll. Molecular correlative studies will be presented. Conclusions: The combination of niclosamide/PDMX1001, Abi and prednisone is well tolerated with promising safety and efficacy data. Targeted serum trough levels of niclosamide are clinically achievable. Clinical trial information: NCT02807805.