Monotherapy Arm Research Articles

795P - A prospective observational study on the optimal maintenance strategy in HER2-positive advanced gastric cancer treated with trastuzumab based therapy

BackgroundTrastuzumab plus chemotherapy is an effective therapy in HER2 positive advanced gastric cancer (AGC). However, the optimal maintenance treatment in patients benefited from the initial therapy remains unclear. MethodsThis was a prospective observational study in patients with untreated HER2 positive AGC. After 6 cycles of trastuzumab combined with chemotherapy, patients who had not progression disease were divided into two arms: trastuzumab monotherapy (arm A) and trastuzumab plus single chemo-agent derived from the initial chemotherapy (arm B). Patients received CT/MRI for response evaluation every 8 weeks or anytime suspected treatment failure. Adverse effects and costs were recorded every cycles. The primary end point was overall survival (OS), secondary end points included progression free survival (PFS), cost-effectiveness ratio per progression-free life-year saved (PF-LYS) and safety. ResultsIn total, 115 HER2 positive AGC treated with trastuzumab based first line chemotherapy were registered. After 6 cycles, 78 patients (6 CR, 46 PR, 26 SD) were eligible: 30 patients were in arm A accepted trastuzumab monotherapy as their maintenance therapy, 48 were in arm B. The clinicalpathological characteristics of two arms were well balanced. There was no significant differences of median OS (16.5 vs 20.0 months, P=0.169) or PFS (7.9 vs 11.0, P=0.892) between two arms. Adverse effects were also similar including cardiac safety. Subgroup analysis showed chemotherapy additional to trastuzumab benefited on OS in patients who had stable disease (SD) of response (HR: 0.084, P=0.004), without liver metastasis (HR:0.271, P=0.008) or less than 2 organs of distance metastatic (HR: 0.263, P=0.005). The average cost per patients in arm A was 153,137 RMB and 165,195 RMB in arm B. While, PF-LYS in arm A was 1.29 times higher than arm B (19,384 vs 15,018 RMB). ConclusionsBoth maintenance therapy strategies are optional for patients who benefit from the initial 6 cycles of therapy. However, there is an advantage on PF-LYS in patients treated with trastuaumab plus single chemotherapy agent. Furthermore, continual single-chemotherapy agent was beneficial in Patients with certain characterisitic. Legal entity responsible for the studyZhongshan Hospital, Fudan University. FundingShanghai Science and Technology Funds 1741195400. DisclosureAll authors have declared no conflicts of interest.

913PD - APACHE: An open label, randomized, phase II study of durvalumab (Durva), alone or in combination with tremelimumab (Treme), in patients (pts) with refractory germ cell tumours (GCT): Results from the expanded combination therapy cohort

BackgroundInterim results from APACHE (NCT03081923) have been presented, with the monotherapy arm stopped for futility (Necchi, Eur Urol 2018). Updated results with the expanded combination therapy cohort are presented. MethodsApache is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 chemotherapy (CT) regimens received Durva, 1.5gr q4w, x 13 cycles (arm A) or Durva plus with Treme, 75mg q4w, x 4 cycles, followed by Durva alone x total 13 cycles (arm B). The primary endpoint is the modified objective response-rate (mORR=RECIST 1.1 complete or partial response [PR] or stable disease [SD]+STM reduction >10%). H0: mORR rate ≤10%, H1: mORR ≥25% (α and β=10%). The total sample size of 120 pts is split into 3 stages: in stage 1, each arm is terminated whenever no response is observed in 11 pts/arm. In stage 2, 29 additional pts/arm are enrolled. Biomarker analyses include: PD-L1 expression on immune cells (Ventana SP142) and comprehensive genomic profiling (CGP) with FoundationOne assay. ResultsFrom 02/17-11/18, 29 pts were enrolled (11 arm A and 18 arm B). 22 had gonadal and 7 extragonadal GCT, 19 had received >/=3 prior CT regimens. Median tumour mutational burden (TMB) was 4 mutations (mut)/mb, 1pt showed microsatellite instability in arm A. 10 pts (34.5%) experienced any-Grade AEs, without differences between arms. In the expanded arm B, 2 responses (11.1%, 1 RECIST-PR in seminoma and 1 SD with STM reduction in nonseminoma) and 2 SD were observed. PD occurred regardless of PD-L1 expression and TMB. After median follow-up of 16.3 months, 12-month OS in arm A was 30% (95%CI: 7.2-57.7) and in arm B was 29.6% (95%CI: 10.2-52.2). Further CT post-PD was administered in 8 pts (27.6%), but was mostly ineffective (7/8 SD/PD). ConclusionsDespite objective responses were rare with IO, long-term OS results are encouraging in very highly pre-treated GCT pts, suggesting a role for maintenance approach in earlier setting (2nd-line CT), and privileging Durva+Treme due to more responses. Conventional IO biomarkers did not allow for patient selection, and further research is warranted. Clinical trial identificationNCT03081923. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureS.M. Ali: Full / Part-time employment: Foundation Medicine. J. Chung: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. A. Necchi: Honoraria (institution), Advisory / Consultancy: Merck; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Spouse / Financial dependant: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Clovis; Honoraria (institution), Advisory / Consultancy: Janssen; Honoraria (institution), Advisory / Consultancy: Roche. All other authors have declared no conflicts of interest.

Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial

BackgroundThe biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed.MethodsPostmenopausal women with untreated stage I–III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures.ResultsSixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1–2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (− 73.2%) was superior to both monotherapy arms combined (− 49.9%; p = 0.001) and mVNB (− 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (− 73.2%) was numerically higher compared to LTZ (− 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases.ConclusionsShort-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted.Trial registrationNCT02802748, registered 16 June 2016.

P14.54 Association of EGFR Expression and Copy Number with Outcome in Depatux-m (ABT-414) Randomized Phase II Study of the EORTC Brain Tumor Group

Abstract BACKGROUND Patients with glioblastoma (GBM) have a dismal prognosis and are in desperate need of better therapy than the standard of care (SOC). Epidermal growth factor receptor (EGFR) gene amplification is reported in more than 50% of GBMs as an important target for therapeutic intervention and as a potential predictive biomarker. Depatuxizumab mafodotin (depatux-m, ABT-414) is an antibody-drug conjugate that preferentially binds cells with EGFR active conformation, internalized and releases the cytotoxin, leading to cell death. In the primary analysis we reported a trend (in EORTC 1410; HR: 0.71, 95% CI [0.50–1.02], p = 0.06) at topline analysis which continued to improve with ad hoc follow up (HR of 0.66, 95%CI [0.47–0.93]; p = 0.016) was observed towards improved overall survival (OS) in patients with EGFR amplified (amp) recurrent glioblastoma treated with depatux-m in combination with temozolomide. OS was equivalent in the depatux-m monotherapy and chemotherapy control arms. Here, we evaluate the association of EGFR mRNA expression and EGFR copy number with outcome using the updated efficacy data. METHODS Eligible were patients with centrally confirmed EGFR amp GBM at first recurrence after temozolomide chemo-irradiation. Patients were randomized to either a) depatux-m 1.0–1.25 mg/kg combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, b) depatux-m 1.0–1.25 mg/kg monotherapy or c) either temozolomide or lomustine (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Long-term follow-up data (24 months follow-up; 237 events) were utilized for this EGFR analysis. The expression level of EGFR was determined using RT-PCR. The absolute copy number of EGFR was determined using next generation sequencing. EGFR mRNA and EGFR copy number were treated as continuous variables and compared to OS using a generalized additive cox proportional hazards model. RESULTS The outcome of the long-term follow-up was that when used in combination with TMZ, depatux-m addition resulted in improved OS as compared to TMZ/ LOM control regardless of EGFR expression or absolute copy number of EGFR. In contrast, in depatux-m monotherapy, a trend was observed that depatux-m improved the outcome only at highest expression levels and highest absolute EGFR copy number. CONCLUSIONS The long-term follow-up trial results demonstrated that addition of depatux-m to SOC showed a trend to increased survival as compared to SOC alone in EGFR amp patients as determined using Fluorescent in situ hybridization (FISH) analysis. Further retrospective analysis supports this efficacy advantage is observed at all expression and amplification levels. When used in combination with SOC and regardless of the absolute copy number of EGFR, the trend for OS improvement was observed at all expression levels.

Cytopenias among patients with rheumatic diseases using methotrexate: a meta-analysis of randomized controlled clinical trials.

To conduct a systematic literature review and meta-analysis to estimate the incidence of anaemia, leucopoenia, neutropenia and thrombocytopenia associated with MTX plus folic acid among patients with rheumatic diseases. We searched MEDLINE, PubMed and EMBASE through August 2016 for all randomized controlled clinical trials with a MTX monotherapy arm. We excluded randomized controlled clinical trials for cancer and included only double-blind studies that reported on haematologic adverse events. Studies were excluded if patients did not receive folic acid or leucovorin supplementation. Full text articles were assessed by two independent reviewers. Incidence estimates were calculated using random-effects models. Of 1601 studies identified, 30 (1.87%) were included, representing 3858 patients; all had RA. Seventeen trials reported on anaemia (n = 2032), 17 reported on leucopoenia (n = 2220), 16 reported on neutropenia (n = 2202) and 12 reported on thrombocytopenia (n = 1507). The incidence for any anaemia was 2.55% (95% CI 0.60-5.47%), any leucopoenia 1.17% (95% CI 0.16-2.80%), any neutropenia 1.77% (95% CI 0.33-4.00%), and any thrombocytopenia 0.19% (95% CI 0.00-0.86%). Four cases of severe anaemia were reported, as defined by authors, along with three cases of severe neutropenia. No cases of severe leucopoenia, severe thrombocytopenia or pancytopenia were reported. Cytopenias are an uncommon side effect of low-dose MTX with folic acid supplementation among RA patients. Further research is needed to reach a more precise estimate.

Combination Therapy With Anti-PD-1 and Anti-B- and T-lymphocyte attenuator Results in a Synergistic Therapeutic Effect Against Murine Glioblastoma

Abstract INTRODUCTION The immune checkpoint molecule programmed cell death protein-1 (PD-1) has been the mainstay target of immunotherapy. However, the recent CheckMate 143 trial involving antibodies against PD-1 (anti-PD-1) failed to meet its primary endpoint of improved overall survival in patients with glioblastoma (GBM). In part, this issue may be due to the expression of alternative checkpoints such as B- and T-lymphocyte attenuator (BTLA) on several immune cell types, including cytotoxic and regulatory T cells. Several murine GBM models such as GL261 and CT2A indicate that there is significant upregulation of BTLA in tumors with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. METHODS C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Additionally, flow cytometric analysis of blood and brains were done on days 7 and 16 post-tumor implantation. RESULTS Tumor-bearing mice treated with dual anti-PD-1 and anti-BTLA therapy experienced improved overall survival (75%) compared to anti-PD-1 (25%) or anti-BTLA (0%) alone (P = .008). Compared to monotherapy arms, mice treated with combination therapy also demonstrated increased levels of CD8 + cytotoxic T cells as well as decreased levels of CD4 + Foxp3 + regulatory T cells on day 7 in the blood and day 16 in the brain (P &lt; .05). CONCLUSION This is the first preclinical investigation into the effects of combining anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on integral immune cell populations such as anti-tumor CD8 + T cells and immunosuppressive regulatory T cells through this dual therapy.

Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC. To evaluate the safety and efficacy of the anti-PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC. Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil-based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available. Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects. Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm. Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status. Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A. ClinicalTrials.gov identifier: NCT02558894.

Simple methods for the estimation and sensitivity analysis of principal strata effects using marginal structural models: Application to a bone fracture prevention trial.

In randomized clinical trials, it is often of interest to estimate the effect of treatment on quality of life (QOL), in addition to those on the event itself. When an event occurs in some patients prior to QOL score assessment, investigators may compare QOL scores between patient subgroups defined by the event after randomization. However, owing to postrandomization selection bias, this analysis can mislead investigators about treatment efficacy and result in paradoxical findings. The recent Japanese Osteoporosis Intervention Trial (JOINT-02), which compared the benefits of a combination therapy for fracture prevention with those of a monotherapy, exemplifies the case in point; the average QOL score was higher in the combination therapy arm for the unfractured subgroup but was lower for the fractured subgroup. To address this issue, principal strata effects (PSEs), which are treatment effects estimated within subgroups of individuals stratified by potential intermediate variable, have been discussed in the literature. In this paper, we describe a simple procedure for estimating the PSEs using marginal structural models. This procedure utilizes SAS code for the estimation. In addition, we present a simple sensitivity analysis method for examining the resulting estimates. The analyses of JOINT-02 data using these methods revealed that QOL scores were higher in the combination therapy arm than in the monotherapy arm for both subgroups.

Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

AbstractThis open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.

Phase 3 (COSMIC-312) study of cabozantinib in combination with atezolizumab vs sorafenib in patients with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy

Phase 3 (COSMIC-312) study of cabozantinib in combination with atezolizumab vs sorafenib in patients with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy

Abstract CT007: Safety and immunogenicity of a personalized neoantigen-Listeria vaccine in cancer patients

Abstract Background. Meaningful anti-tumor immunity in cancer patients (pts) has been associated with the presence of specific T cells directed at neoantigens, a class of unique peptides that arise from tumor-specific mutations. ADXS-NEO, a personalized Listeria monocytogenes (Lm)-based immunotherapy, is a bioengineered Lmthat secretes an antigen-adjuvant fusion protein consisting of ≥ 20 unique (personal) neoantigens and a truncated fragment of listeriolysin O (tLLO), which has adjuvant properties. Preliminary safety and immunogenicity results from an ongoing Phase I trial with ADXS-NEO are herein reported. Methods. ADXS-NEO-02 is a Phase I dose-escalation study of ADXS-NEO in subjects with metastatic microsatellite stable colon cancer (CRC), metastatic squamous histology head and neck cancer, and metastatic non-small cell lung cancer (NSCLC). Manufacturing of ADXS-NEO starts with whole exome sequencing of each pt-matched normal and tumor samples to detect genetic alterations in the coding regions of the genome followed by its production under GMP specifications. ADXS-NEO is infused intravenously every 3 weeks until disease progression or limiting toxicity. Main endpoints include safety, tolerability and immune-correlative data. Results. The turnaround time for manufacturing ADXS-NEO has consistently been ≤ 8 weeks from biopsy to first dose. Two pts treated at 1X109 CFU (dose level 1) experienced dose limiting toxicities (i.e., Gr 3 hypoxia ± Gr 3 hypotension) within 4 hours of completing the infusion of the second dose. These acute adverse events correlated with elevation of serum IL-6 and other cytokines, and both cases were manageable and reversible with tocilizumab and/or steroids. A dose de-escalation cohort was initiated at 1X108 CFU, which has been found to be safe and tolerated by one pt. In these pts, ADXS-NEO induced: 1) activation and proliferation of CD4+ / CD8+ T cells; 2) neoantigen-specific T cell responses after 1 week of the initial priming dose and 3) antigen spreading and T cell responses to neoantigens not selected by algorithm. Conclusions. ADXS-NEO at 1X109 CFU was beyond the maximum tolerated dose but it was effective in eliciting a fast and broad anti-tumor immunity, including T cell responses to neoantigens and antigen spreading. Enrollment continues both in monotherapy and combination therapy arms with anti-PD-1/PD-L1 therapy, to define the recommended Phase II dose. Citation Format: J. Randolph Hecht, Jonathan W. Goldman, Sandy Hayes, David Balli, Michael F. Princiotta, Justin G. Dennie, John Heyburn, Tammy Sands, Sumitra Sheeri, Robert Petit, Andres A. Gutierrez, Frank Tsai. Safety and immunogenicity of a personalized neoantigen-Listeria vaccine in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT007.

Abstract 4100: Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy

Abstract Background: In patients undergoing chemotherapy and/or immune therapy, endogenous T cells within the tumor micro-environment (TME) and in the periphery are subject to dynamic changes. Particularly, exhausted T cells in the TME and peripheral blood mononuclear cells (PBMCs) isolated from whole blood express the inhibitory receptor, Programmed Cell Death Receptor 1 (PD-1). A small but significant number of these T cells can recognize neo-epitopes (neoE) arising from patient specific mutations. We determined receptor occupancy (RO) in patients treated with monoclonal anti-PD-1 antibody AB122, which is currently in clinical development. Methods: Multi-color flow cytometry was used to determine RO post-AB122 administration using a directly-conjugated competitive antibody to AB122. In addition, we determined RO values using the established method for nivolumab using a biotinylated anti-human IgG4 to detect bound anti-PD-1. The assays were also optimized to determine RO in whole blood from patients with solid tumors treated with AB122. Receptor occupancy using both methods were compared. Further, whole exome sequencing from archival formalin-fixed, paraffin-embedded (FFPE) tissue was performed and T cells that recognized patient-specific neoE resulting from tumor-specific mutations were identified in patient blood. Results: In the dose-escalation study for AB122 monotherapy arm, a variety of dosing regimens have been evaluated, including Q2W, Q3W and Q4W. The number of doses received ranged from 1 to 20. Data from patients in the 80 and 240 mg Q2W cohorts showed that AB122 serum concentrations ≥1.5 μg/mL (equivalent to 10 nM) are associated with full receptor occupancy. The RO associated with AB122 dosing is maintained when dosed in combination with the potent A2aR/A2bR dual adenosine receptor antagonist AB928 in an ongoing clinical trial. Conclusions: Full RO is observed with both cohorts of AB122 monotherapy (80 and 240 mg Q2W) and in the 240 mg Q2W combination with AB928. Study of peripheral target engagement and expansion of neoE-specific T cell populations in a longitudinal study of solid tumor patients treated with AB122 could provide insight towards designing successful combination immune therapy regimens in future clinical trials with AB122. Citation Format: Devika Ashok, Songming Peng, Benjamin Yuen, Matt Walters, Stephen W. Young, Lisa Seitz. Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4100.

Abstract CT112: A Phase I multicenter trial of the dual MDM2/MDMX inhibitor ALRN-6924 in children and young adults with relapsed/refractory pediatric cancers

Abstract BACKGROUND: TP53 mutations are rare across pediatric cancers. Recent work using CRISPR-Cas9 screens has demonstrated that MDM2 and MDMX are strong dependencies in a range of TP53-wildtype pediatric malignancies. Increased expression of MDM2 and MDMX is a common mechanism for suppressing p53 in pediatric malignancies and can occur by copy number gain or amplification, as has been reported in retinoblastoma and hepatoblastoma. In pediatric high-grade gliomas, activating PPM1D mutations drive p53 suppression, likely through MDM2 stabilization. ALRN-6924 is a novel, first-in-class, cell-permeating stapled peptide that disrupts the inhibitory interactions between MDM2/MDMX(MDM4) and p53. ALRN-6924 has been evaluated in two adult Phase I trials, with good tolerability and evidence of clinical activity across a range of cancer subtypes. Given the oncogenic roles of MDM2 and MDMX in pediatric malignancies, we developed a Phase I clinical trial designed to evaluate the tolerability, pharmacokinetics, and pharmacodynamic and antitumor activity of ALRN-6924. METHODS: This is a Phase I, open-label, investigator-initiated multicenter study of ALRN-6924 in children 1-21 years of age with relapsed/refractory cancer (NCT03654716). The primary objectives are to determine the recommended phase 2 dose, and to describe toxicities and pharmacokinetic parameters of ALRN-6924 in this population. The monotherapy arm consists of two cohorts: Cohort A for patients with TP53-wildtype solid tumors and lymphomas; and Cohort B for patients with retinoblastoma, or TP53-wildtype tumors that meet any of the following criteria: hepatoblastoma, malignant rhabdoid tumor, MDM2 or MDMX amplification, TET2 loss, or PPM1D activating mutations. Patients with CNS primary tumors are only eligible for Cohort B. In Cohorts A and B, patients receive ALRN-6924 intravenously on Days 1, 4, 8 and 11 of a 21-day cycle starting at a dose of 2.2 mg/kg. An expansion cohort for patients eligible for Cohort B will open following completion of monotherapy dose escalation. Patients with relapsed/refractory leukemias enroll to Cohort C and receive ALRN-6924 in combination with low-dose cytarabine on days 1, 8 and 15 of a 28-day cycle starting at a dose of 2.7 mg/kg. Pharmacokinetic sampling and pharmacodynamic testing (serum MIC-1 modulation) is required for all patients. Correlative biology studies will include evaluation of circulating tumor DNA for TP53 mutations in patients with solid tumors and serial assessment of leukemic blasts in patients with relapsed leukemia. Enrollment began in October 2018. Up to 69 patients will be enrolled. Citation Format: David S. Shulman, Kieuhoa T. Vo, Elizabeth Fox, Jodi A. Muscal, Loren D. Walensky, Yana Pikman, Kimberly Stegmaier, Alanna Church, Brian D. Crompton, Andrew E. Place, Susan N. Chi, Allison F. O'Neill, Junne Kamihara, Suzanne Ezrre, Cecilia Carlowicz, Dawn Pinchasik, Hasan Al-Sayegh, Clement Ma, Wendy B. London, Steven G. DuBois. A Phase I multicenter trial of the dual MDM2/MDMX inhibitor ALRN-6924 in children and young adults with relapsed/refractory pediatric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT112.

S831 CPI‐0610, A BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) INHIBITOR, REDUCES PRO‐INFLAMMATORY CYTOKINES, BONE MARROW FIBROSIS AND THE NUMBER OF TRANSFUSIONS IN MYELOFIBROSIS PATIENTS

Background:Myelofibrosis (MF) is a myeloproliferative neoplasm associated with a cytokine (CK) milieu that leads to bone marrow (BM) fibrosis. Ruxolitinib (RUX) is the only approved therapy for MF, but patients (pts) can eventually relapse/have inadequate response. RUX can also worsen anemia and pts may require transfusions. BET proteins are transcriptional regulators that control key oncogenic pathways, including NF‐κB, MYC, and BCL2 and TGFβ signaling, an important driver of fibrosis. Preclinical studies suggest that a combination of a BET inhibitor (BETi) and RUX results in a synergistic reduction of the hallmarks of MF: splenomegaly, BM fibrosis and the mutant (MUT) allele burden (Kleppe 2018). CPI‐0610 is a selective and potent BETi that impacts megakaryocyte differentiation (unpublished data), cells responsible for pro‐inflammatory CK production and is currently being evaluated in MF, alone or in combination with RUX in a clinical trial with 3 arms: CPI‐0610 alone (Arm 1), CPI‐0610+RUX in pts exposed to RUX/with an inadequate response to RUX (Arm 2), or CPI‐0610+RUX in JAKi naïve pts with anemia (Arm 3). Arm 1 and 2 are stratified between transfusion dependence (TD) and splenomegaly at baseline.Aims:Phase 2 study to assess CPI‐0610 alone or “add‐on” to RUX in MF pts. Primary endpoints: conversion of TD to transfusion independence (TI), spleen volume response, patient reported outcomes, safety and PK. Additional endpoints include: changes in pro‐inflammatory CK levels, BM fibrosis and MUT profiling.Methods:Pt samples were used to analyze CK levels, MUT profiles and BM fibrosis. CK analyses utilized Myriad‐RBM InflammationMAP and CustomMAP and MUT analysis utilized the Rapid Heme Panel (Kluk, 2016).Results:23 pts were accrued to this multi‐center study, with 18 pts analyzed: MUT profiles which revealed the following MUT: 11 ASXL1(61%), 10 JAK2(56%), 6 CALR (33%) and 2 MPL(11%). 10 pts (56%) had at least 3 MUTs and 17 pts (94%) had at least one driver MUT (JAK2, CALR or MPL). 1 pt (6%) was triple negative and 12 pts (67%) had a high MUT profile (HMR). Baseline CK levels were elevated, in pts who failed/inadequate response to RUX. CPI‐0610 at a starting dose of 125 mg QD (days 1–14 of 21‐day cycle) reduced CK levels in both monotherapy and combination arms. Suppression of IL‐18 was observed in all pts analyzed (n = 8) with &gt;50% decrease in 4/8 pts. Trends were also observed for a number of other CK, including IL‐8 and CRP. CK inhibition was sustained over multiple cycles of CPI‐0610 (combination/monotherapy). Best spleen volume reduction ranged from 6–44% in 10 pts. Out of the 4 pts with BM assessments (pre and at least 1 post), 2 were TD at baseline. Three pts had one grade improvement in BM fibrosis (1 at 6 mth, 2 at 1 yr) and had Hgb increases of ≥1.5 g/dL for ≥12 weeks without transfusions. The other pt had a 1 grade improvement in the BM reticulin score (at 6 mth). Moreover, both of the TD pts became TI. Hepcidin levels and PK will be presented. The most common adverse events were Grade 1/2 diarrhea, nausea/vomiting and reversible and non‐cumulative thrombocytopenia.Summary/Conclusion:CPI‐0610 alone or in combination with Rux demonstrates encouraging clinical activity (spleen responses, conversion to TI and improvement in BM fibrosis) with good tolerability. Assessment of CK levels suggest that CPI‐0610 therapy durably reduces pro‐inflammatory CK. Notably, levels of individual CK were reduced to levels observed in normal healthy donors and were maintained during treatment. Genomic profiling data shows that majority of pts had HMR MUT at baseline. Updated data will be presented.image

How to approach CLL in clinical practice.

How to approach CLL in clinical practice.

A dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of mTORC1/2 inhibitor XP-105 (BI 860585) as monotherapy and in combination with exemestane or paclitaxel in patients (pts) with advanced solid tumors.

3127 Background: Resistance to mTORC1 inhibition may develop through feedback loop leading to upregulation of mTORC2. XP-105, also known as BI 860585, is a potent dual mTORC1/2 inhibitor designed to overcome such resistance. This Phase 1 trial (NCT01938846) was performed to determine the MTD and activity of XP-105 alone or in combination with exemestane or paclitaxel in pts with advanced solid tumors. Methods: A 3+3 escalation design was used; Pts received XP-105 (5–300 mg/day) monotherapy or (40–220 mg/day) combined with fixed-dose exemestane 25 mg/day, or 80–160 mg/day combined with paclitaxel 60 or 80 mg/m2/week. A reduction of pAKT/total AKT ratio was used as a PD marker of target inhibition. Results: 90 pts were treated (41 with monotherapy, 25 and 24 in combination with exemestane, or paclitaxel respectively). XP-105 MTD was defined as 220 mg daily for monotherapy, and 160mg daily with exemestane 25 mg/d or paclitaxel 80 mg/m2/week. In the monotherapy arm, stable disease (SD) was reported in 8 pts (20%), with a median duration of 11 months. In the exemestane combination arm, 4 (16%) partial responses (PR) were reported. In the paclitaxel combination arm, 1 complete response (CR) and 4 PRs were reported (OR rate 21%). Disease control rate (CR/PR/SD) was 20%, 28%, and 58% in the monotherapy, XP-105/exemestane, and XP-105/paclitaxel arms, respectively. A sustained reduction in pAKT/total AKT to &lt; 50% of baseline levels was observed with XP-105 ≥120mg daily. Overall, XP-105 was well tolerated; in the XP-105/paclitaxel combination the most frequent drug-related AEs were diarrhea and fatigue (58.3% each), hyperglycaemia (54.2%), anaemia (50%). Grade ≥3 AEs were hyperglycaemia, fatigue, diarrhea, anaemia, leukopenia. No PK interaction was observed. Conclusions: The MTD for XP-105 monotherapy and in combination with exemestane or paclitaxel was defined as 220 mg and 160mg once daily, respectively. Combination regimens showed higher activity as compared to monotherapy with durable OR in about 20% of pts. The observed safety profile of XP-105 compared favorably to those reported from other mTOR inhibitors. Clinical trial information: NCT01938846.

A phase II study of cpi-0610, a bromodomain and extraterminal protein inhibitor (BETi) alone or with ruxolitinib (RUX), in patients with myelofibrosis (MF).

7056 Background: BETi have been shown to regulate NF-κB, MYC, BCL2, and TGF-β signaling, important drivers of marrow fibrosis. Preclinical studies have suggested that combined BETi and JAK2 inhibition synergistically reduce MF-related splenomegaly, bone marrow fibrosis and the malignant allele burden (Kleppe, 2018). CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). Arms 1 and 2 are stratified: transfusion dependence (TD) yes: A/no: B. The primary objectives are to evaluate the effect of CPI-0610 on transfusion dependence (TD, 1A and 2A) and spleen volume (1B, 2B and 3). A Simon two-stage design: if 2 responses are seen will advance to the 2nd stage. Results: 4 pts enrolled in Arm 1, 14 pts in Arm 2, no pts accrued to Arm 3 yet. Median age: 69 years (46-83), gender: 9 male pts; 11 pts received ≥1 prior therapy besides RUX. JAK2/MPL/CALR mutations: 17/18 pts, ≥3 mutations: 10 pts, ASXL1 mutations: 11 (61%) pts. Hemoglobin &lt;10 g/dL at baseline: 11 (61%) pts. 6 pts received ≥ 24 weeks of CPI-0610 treatment at this analysis. 2 TD pts in Arm 2 became transfusion independent, both remain on treatment free of transfusions. Hgb increase of ≥1.5 g/dL from baseline was observed with successive cycles of therapy in anemic pts: 2/2 pts in Arm 1 (100%) and 3/9 pts in Arm 2, (33%). Spleen volume reduction, by MRI (6-44%) was observed in all 10 evaluable pts irrespective of their driver mutation. Symptom improvement and reductions of cytokine levels were observed. In Arm 1: 2/2 evaluable pts had marrow fibrosis improvement with Hgb increase; additionally, thrombocytosis resolved in 2/2 pts (baseline ≥791 103/uL). Most common adverse events were mild diarrhea, nausea/vomiting; and reversible and non-cumulative thrombocytopenia. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. Collectively, these data indicate that CPI-0610 +/- RUX might have disease modifying effects. Updated data will be provided. Clinical trial information: NCT02158858.

Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.

TPS4142 Background: Perioperative FLOT chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient outcomes are still unsatisfactory and 5-year survival in T3-4 or nodal positive disease is still around 50%. Targeting the PD-1/PD-L1 pathway has proven active in different cancers, including esophagogastric cancer, and was associated with response rates in the 10-15% range in unselected, heavily pre-treated gastric cancer patients. Atezolizumab is a PD-L1 inhibitor with established efficacy and tolerability profiles. This study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with FLOT. Methods: This is a large, multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Eligibility status is centrally evaluated. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS) as assessed by the Kaplan-Meier-Method. The statistical design is based on a target HR of 0.68, a power of 0.8, and a significance level of p&lt; 0.05 (1-sided log rank test). A total of 295 patients will be randomized. Main secondary endpoints are rates of centrally assessed pathological regression (rates of complete and nearly complete pathological regression), overall survival, R0 resection, and safety. Recruitment started in Sept 2018; by February 2019, a total of 27 patients have been randomized. Clinical trial information: NCT03421288.

A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.

Biomarker driven phase II umbrella trial study of AZD1775, AZD2014, AZD2811 monotherapy in relapsed small cell lung cancer.

8514 Background: Recent progress in genomic profiling of small cell lung cancer (SCLC) has demonstrated that a high proportion of SCLC harbor mutations in cell cycle-related genes and RICTOR amplification. With the recent introduction of cell-cycle altering small molecules, AZD1775 (WEE1 inhibitor), AZD2811 (aurora kinase B inhibitor) and mTOR1/2 inhibitor (AZD2014), biomarker-driven umbrella study is being conducted in relapsed SCLC. Methods: This is a phase II umbrella trial study with multiple monotherapy arms in resistant SCLC who has failed prior platinum-based chemotherapy and known genomic profile from pre-designed screening study of SUKSES-S (Small cell lung cancer Umbrella Korea StudiES, NCT02688894). Patients with MYC family amplification or co-alteration in CDKN2A and TP53 were allocated to SUKSES-C (AZD1775 arm, NCT02593019); RICTOR amplification to SUKSES-D (AZD2014 arm, NCT03106155). Otherwise, patients were randomly assigned to non-biomarker specific arms, SUKSES-N1 (AZD1775 arm, NCT02593019) or SUKSES-N3 (AZD2811 arm, NCT03366675). Each cohort was designed as Simon 2-stage scheme. Results: Patients allocated to SUKSES-C (n = 7) &amp; N1 (n = 24) showed no objective response rate and stable disease was observed in 3 patients (42.9%) and 6 patients (25.0%), respectively. The median progression-free survival (PFS) was 1.28 months (95% confidential interval [CI] 1.18–not available [NA]) and 1.21 months (95%CI 1.15-2.33), respectively. SUKSES-D (n = 4) showed no objective response as well as no stable disease with PFS of 1.25 months (95%CI 0.98-NA). SUKSES-N3 (n = 15) showed no objective response with 5 stable disease (33.3%) and PFS of 1.61 months (95%CI 1.18-NA). For the safety record, adverse events (AEs) grade≥3 were observed as follows: SUKSES-C &amp; -N1 (n = 1, 3.2%), -D (n = 3, 75.0%), -N3 (n = 9, 60%). Notably, neutropenia (grade≥3) was frequently observed (n = 8, 53.3%) in AZD2811 arm including a case of septic shock. Conclusions: SUKSES is the first biomarker-driven umbrella study with the largest cohort of genomic profile pre-screened in resistant SCLC patients (n = 275). However, it does not support further development of the current regimens of AZD1775, AZD2811, AZD2014. Altered administration schedule or combination regimen is under development. Clinical trial information: NCT02593019, NCT03106155, NCT03366675.