A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma

Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638. Registered 07 November 2013.

Management of Pregnancy in Rheumatic Disease

Managing patients with rheumatic diseases (RMD) during pregnancy and the postpartum period can be a challenge for both rheumatologists and obstetricians. While disease activity during the course of pregnancy varies with regard to the presence of underlying conditions, maintenance of remission from conception through to delivery increases the chances of an uncomplicated pregnancy. A period of remission of at least 6 months prior to conception increases the chance of a successful conception while decreasing the risk of flares during pregnancy. For this reason, discussion of pregnancy in females with RMDs should begin prior to conception with risk stratification and pregnancy planning. This allows for the transfer to pregnancy-compatible medications, disease stabilisation, determination of autoantibody status, and evaluation of end-organ damage. During pregnancy, where possible, disease activity should be monitored with scores modified to allow use in pregnancy. Prompt recognition and treatment of active disease is essential to minimise the risk to the pregnancy. Systemic lupus erythematosus and axial spondyloarthropathy can present diagnostic dilemmas due to overlap of symptoms of disease activity and normal pregnancy. Patients with end-organ involvement, such as systemic lupus erythematosus or systemic sclerosis, face a higher risk of adverse pregnancy outcomes and disease progression. Close monitoring of patients with RMD should be done by both obstetrics and rheumatology, with regular communication between specialties. Medications should be reviewed at each stage of pregnancy to ensure compliance with the current American College of Rheumatology (ACR) guidelines and the adequate treatment of RMDs.

Case Report: Epstein-Barr virus Positive Gastric Carcinoma

In 2014, The Cancer Genome Atlas provided a molecular classification defining Epstein-Barr virus (EBV)-positive gastric cancer as a separate subtype. While its prognostic role is still debatable, emerging potential biomarker role for personalized treatment strategies is already recognized by international guidelines. We report a case with successful combined therapy of a 64-year-old EBV-positive gastric cancer male patient. Patient initially presented with locally advanced gastric cancer, which was treated surgically; three years later patient developed recurrence within the remnant stomach and was treated surgically. Two years after operation patient developed distant metastases and was enrolled in a clinical trials’ (NCT01630083) arm 2: receiving chemotherapy and monoclonal antibody claudiximab. This treatment induced durable disease stabilisation for 34 months. After progression, second line chemotherapy with docetaxel and cisplatin provided additional disease stabilisation and symptom control for 8 months. Patient’s overall survival reached 9.1 years. Presented report shows EBV- ositive gastric cancer case with better overall survival compared to reported average, which contributes to the meaningfulness of its distinction as a separate subtype, evidence that targeted therapy is more effective in selected patient groups, and EBV as an emerging biomarker.

Benefit from anti-EGFRs in RAS and BRAF wild-type metastatic transverse colon cancer: a clinical and molecular proof of concept study

ObjectivePrimary tumour location is regarded as a reliable surrogate of colorectal cancer biology. Sensitivity to anti-EGFRs (Epidermal Growth Factor Receptor) of metastatic transverse colon cancers (mTCCs) has usually been assumed similar to right-sided tumours; however, evidence about the clinical behaviour of mTCC is limited. Thus, to verify sensitivity of mTCC to anti-EGFRs we conducted the present study.MethodsPatients with RAS/BRAF wild-type microsatellite stable (MSS) mTCC receiving anti-EGFR monotherapy, or in combination with irinotecan if clearly irinotecan-refractory, were included. Hypothesising an overall response rate (ORR) of 35%, 11 patients, of whom at least 3 were responders, were necessary to be able to reject the null hypothesis of an ORR of 5%, with α and β errors of 0.05 and 0.20. PRESSING panel and consensus molecular subtypes (CMS) were assessed on tumour samples, whereas in-silico data were obtained from TCGA dataset.ResultsAmong nine eligible patients, four and three achieved response and disease stabilisation (ORR 44%). At a median follow-up of 23.1 months, median progression-free survival and overall survival were 7.3 (95% CI 3.9 to NA) and 15.0 months (95% CI 10.0 to NA), respectively. A MET amplification and an ERBB4 S303F substitution were detected in patients with rapid disease progression, while others had PRESSING panel-negative tumours with CMS2 or CMS4 subtypes.ConclusionsRAS/BRAF wild-type MSS mTCCs may be sensitive to anti-EGFRs, as confirmed by molecular analyses.

Immunotherapeutic Interleukin-6 or Interleukin-6 Receptor Blockade in Cancer: Challenges and Opportunities

Interleukin 6 (IL-6), a well-known pro-inflammatory cytokine with pleiotropic activity is a central player in chronic inflammatory diseases including cancers. Therefore, blockade of the IL-6 signalling pathway has become a target for the therapy of diverse cancers such as multicentric Castleman’s disease (CD), multiple myeloma and solid tumours including renal, prostate, lung, colorectal and ovarian cancers. Monoclonal antibodies against IL-6 (Siltuximab) and the IL-6 receptor (IL-6R) (Tocilizumab) have emerged as potential immunotherapies, alone or in combination with conventional chemotherapy. Human trials have demonstrated the ability to block IL-6 activity and in multicentric CD lead to durable clinical response and longer disease stabilisation. However, the efficacy of these treatments is still debatable for other cancers. New generation therapeutics in development such as Clazakizumab, Sarilumab, and soluble gp130-Fc have the additional features of improved binding affinity, better specificity with reduced adverse effects. A deeper understanding of the immunological basis of these agents, as well as of the challenges that are faced by immunotherapy-based products in clinical trials, will help select the most promising anti-IL-6/IL-6R therapies for large scale use. Concurrently, current research efforts to personalize treatments may help in the treatment of patients that would greatly benefit from IL-6 blocking therapies.

Advanced Adrenocortical Carcinoma – What to do when First-Line Therapy Fails?

Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression-free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease.

Predictors of outcome in patients treated with peptide radio-labelled receptor target therapy (PRRT).

4090 Background: The efficacy of peptide-radiolabelled receptor targeted therapy (PRRT) in patients with well differentiated neuroendocrine tumours has been demonstrated in Phase II and Phase III studies. The recently completed phase IV NETTER-01 demonstrated disease stabilisation or partial response in approximately 80% of patients. However, more studies are needed to identify predictors of PRRT response. We sought to investigate the clinic-pathological characteristics in patients that had radiological progression or death within 12 months of completion of treatment with PRRT. Methods: We performed a retrospective analysis of all patients who had PRRT from 2011-2016. Patient with at least one year of follow-up data from the last treatment dose were included. Patients with evidence of radiological progression within one year of finishing treatment (Group 1) were compared to a similar group with disease stabilisation/response (Group 2)that were matched for age, grade, primary and distribution of metastases. The indication for PRRT was defined as either small volume progression ( < 20%) or progression by RECIST. Results: 307 patients underwent PRRT with Lu-177 or Y-90 DOTATATE during this period. 66 patients in Group 1 were compared to 64 patients in Group 2. There was a significant difference in median overall survival, Group 1 = 21 months compared to Group 2 = 35 months, (p < 0.002). A significantly higher proportion of patients in group 1 had more than 50% liver volume (p < 0.0001). Mean CgA was significantly higher in Group 1, 1250 pg/ml vs 608 pg/ml in Group 2 ( p < 0.03). 18 patients in Group 2 had small volume progression prior to treatment commencement compared to 6 in Group 1 (p < 0.003). Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be conisdered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.

Safety and efficacy of chemosaturation in patients with primary and secondary liver tumours: A single-centre experience after 54 treatments.

e15625 Background: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT Delivery System; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumours while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyse the safety and efficacy of the second generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Methods: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Results: A total of 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors (ocular melanoma [OM] n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1) and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumours had durable disease stabilisation (40%). Median OS, PFS and hPFS were 261, 117 and 135 days, respectively. Tumour volume negatively correlated with OS. Complications and toxicites included thrombopenia, cardiovascular events, ulcerous bleeding and edema. Conclusions: Second generation CS-PHP seems to be effective and tolerable. Patient selection based on tumour volume end entity is of importance. Particularly patients with OM and hepatobiliary tumours represent promising candidates for CS-PHP.

Assessing the value of progression-free survival (AVALPROFS).

187 Background: Controversy exists about progression free survival (PFS) as an endpoint in novel cancer therapy trials. PFS is attractive for practical and methodological reasons but is not always a surrogate for overall survival. It is debatable whether or not PFS has discernable clinical benefit for patients (pts), the main treatment (tmt) goal. Also overlooked are pt perceptions. Few trials directly address if disease stabilisation is worth tmt side effects (SEs) or include relevant patient reported outcome (PRO) measures. AVALPROFS examines longitudinally pts’ understanding of therapeutic intent, PFS and the value placed on drugs that control cancer but have SEs. We report the pilot study here. Methods: The primary pilot aim was to obtain feedback from pts having drugs offering only PFS or modest OS gains, about the acceptability and comprehensibility of PROs for use in a longitudinal study. These included validated quality of life and anxiety measures and 4 study specific interview schedules. In close collaboration with Independent Cancer Patients’ Voices (ICPV) and using an iterative process, draft interviews (pre-tmt, on-tmt, at withdrawal due to toxicity or progression) were developed. Pilot study pts’ clinic consultations were taped prior to home interviews by researchers. Results: 11/19 eligible pts with metastatic breast, lung and head and neck cancers at different treatment phases participated. No pt recalled the phrase PFS being used in consultations. Few knew their latest scan results. Some were confused about the therapeutic aims of further tmt, 4/10 thought it would extend survival. All had experienced or anticipated considerable toxicity. None found the interview schedules too upsetting; all provided comprehensive feedback about these and the trade-off questions. Conclusions: PFS is confusing and questions remain about its true value. Involvement of ICPV in potentially distressing research about study design and PROs at the outset was invaluable. Inclusion of feedback from pilot study pts permitted further refinements to the AVALPROFS study which is currently open and recruiting. Clinical trial information: 16342. [Table: see text]