Search

Background AGOC has a poor prognosis with limited benefits from treatments following failure of chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT). INTEGRATE (phase 2) demonstrated REG effectiveness in prolonging PFS in AGOC pts, with a positive OS trend and less toxicity than other REG trials at the same doses. REG was effective across all regions/subgroups, with regional differences noted in magnitude of effect. INTEGRATE II (phase 3) will explore whether REG is effective in prolonging survival in all patients, and in the Asian sub-population Methods International randomised phase III, double-blind, placebo-controlled trial with 2:1 (REG:placebo)(PBO) randomisation and stratification by tumour location, geographic region, and prior VEGF inhibitors. Histologically confirmed AGOC patients, with evaluable metastatic or locally advanced disease refractory to/relapsed following at least 2 lines of CT, will receive best supportive care plus 160mg REG or matched placebo orally on days 1-21 of each 28 day cycle until disease progression or prohibitive adverse events. Primary endpoint is OS. Secondary endpoints: PFS, response rate, quality of life, safety, identification of prognostic/predictive biomarkers for study endpoints, and REG PK across geographical regions. 350 patients (50% from Asia, with at least 50 patients to be recruited from Japan) randomized in a 2:1 ratio will provide 90% power to detect a hazard ratio (HR) for OS of 0.67 with a 2-sided α of 0.05 assuming PBO median survival is 4.5 mos. The sample size accommodates an interim analysis undertaken once 2/3 of required events have occurred. Results 27 ANZ, 8 Canadian, 15 Korean, 5 Taiwanese, and 2 Japanese sites have been activated with 106 patients enrolled. Remaining Japanese/US sites expected to activate through Q1/Q2 2019.

Background: Androgen deprivation therapy (ADT) with luteinising hormone releasing hormone analogue (LHRHA) or surgical castration alone, or combined with conventional non-steroidal anti-androgen (NSAA), is widely used as initial treatment for hormone-sensitive prostate cancer (PC). Meta-analysis of RCTs showed a 3% absolute improvement in 5 year survival with the addition of a conventional NSAA to a LHRHA or surgical castration. Residual, low level androgen receptor (AR) signalling, or agonist activity from conventional NSAA, may provide a stimulatory signal to hormone-sensitive PC cells. We hypothesize that early use of enzalutamide, a more potent and effective androgen receptor blocker, will reduce residual AR signalling, and improve survival. Aim: To determine the effectiveness of ADT + enzalutamide versus ADT + conventional NSAA, as first-line ADT for M1 PC. Trial design: Open label, randomised, stratified 2-arm, multicentre, intergroup, phase 3 trial Eligibility, stratification, endpoints and statistics Eligibility Stratification Endpoints Statistics Met PC Starting first line ADT Adequate organ function Volume of disease Antiresorptive therapy Comorbidities Study site Overall Survival (Primary) PSA PFS Clinical PFS HRQOL Adverse events ICER 1100 participants 2 yrs accrual 3.5 yrs min f/up 80% power to detect 25% reduction in HR of death from any cause Participants randomised 1:1 to Enzalutamide 160mg daily or conventional NSAA daily until disease progression or prohibitive toxicity. All participants are treated with LHRHA or surgical castration. Assessments at baseline, day 29, week 12, and then every 12 weeks from randomisation until evidence of clinical progression. Imaging with CT scan and WBBS at baseline and evidence of PSA or clinical progression. Tertiary objectives are to identify prognostic / predictive biomarkers. Archival tumour tissue and fasting bloods at baseline, week 24, and 1st progression (PSA/clinical) will be collected. Email: enzamet@ctc.usyd.edu.au Website: http://www.anzup.org.au/ Disclosure: C. Sweeney: Consulting with honoraria to declare with Asetallas, Janssen and Sanofi. All other authors have declared no conflicts of interest.

Background: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was designed to exploit results from whole genome sequencing of pancreatic cancer collected under the auspices of the ICGC in Australia. Results showed that small subsets of patients had actionable changes in their tumor genome that could be druggable with currently available therapies. 93% of cases analyzed harbored a KRAS mutation, KRAS wildtype phenotype may enrich for susceptibility to EGFR inhibition. Her2 positivity occurs in 2% and may confer sensitivity to Her inhibition. Tumors displaying defects in the DNA damage repair pathway (∼5%) respond to DNA damaging chemotherapy. Trial design: The IMPaCT trial is a randomized phase 2 study of first line molecularly guided therapy against standard therapy with gemcitabine in advanced pancreas cancer. We screen potential patients for the three molecular targets: Her2 amplification: trastuzumab+gemcitabine; KRAS wildtype: erlotinib+gemcitabine; and DNA damage: mitomycin C+5-fluorouracil chemotherapy. If a patient's tumour has one of these signals, they consent to be randomized to precision treatment tailored for them or standard therapy with gemcitabine. For analysis, the precision treatment arm will be considered as a whole and compared to the standard therapy arm. In our initial cohort of patients who underwent resection with curative intent, 70% recurred. Recurrence occurred on average 16m after initial surgery. Collection of tissue commenced in 2009. The first site to open was in June 2013 by which time, only 6 patients for whom we had complete sequence data and actionable mutations were still alive, so we changed the trial to screen de novo metastatic patients. Using the WGS data, we constructed a custom sequencing panel for DNA extracted from FFPE core biopsies to screen for mutations in KRAS, BRCA2, BRCA1, PALB2 and ATM. Her2 screening is undertaken with IHC and FISH. We have screened 49 cases, and found 10 with relevant molecular targets, 5 of whom were eligible. The average time from biopsy to delivery of results is 23d, an amendment has allowed patients to commence standard therapy whilst waiting for the results of molecular analysis. The IMPaCT trial is breaking new ground in the treatment of pancreas cancer. Disclosure: All authors have declared no conflicts of interest.

Background: The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) is conducting a randomized trial of accelerated versus standard BEP chemotherapy for intermediate and poor risk metastatic GCTs. This translational substudy will prospectively collect blood and GCT tissue in a centralized biobank. Overall aim: To identify pharmacogenomic and molecular markers of treatment failure, toxicity and overall survival in metastatic GCTs. This could lead to the design of tailored treatments, for example incorporating a higher dose of or an alternative form of chemotherapy. Trial design: Specific objectives: 1. Consent ≤ 500 individuals in our trial for donation of blood and cancer tissue samples for future genomic analyses 2. Collect, process and freeze participant blood (50mL) as whole blood, plasma and serum pre-chemotherapy 3. Collect a representative formalin fixed paraffin embedded (FFPE) block of participant tumour tissue 4. Transport blood and cancer tissue samples to the Chris O'Brien Lifehouse cryostorage facility in Sydney, Australia 5. Establishment of a national biobank for testicular cancer Planned future objectives: Study association of progression (relapse or refractory disease), overall survival and toxicity (as surrogates for excess drug exposure) with genetic polymorphisms known to be involved in: - bleomycin metabolism: BLMH (bleomycin hydrolase gene) variant A1450G SNP - etoposide metabolism and transport: ABCB1 (3435T variant), CYP3A5 - candidate tumour-related markers including DNA methylation profiles of cancer-related genes Conclusions: The ultimate goal of this research is to facilitate a “personalised medicine” approach to the treatment of individuals with advanced germ cell tumours (GCT), with the ultimate goal of curing 100% of patients. We invite researchers with blood or tumour samples, and/or expertise in relevant laboratory techniques to collaborate in future analyses. Email: p3BEP@ctc.usyd.edu.au website: http://www.anzup.org.au Disclosure: All authors have declared no conflicts of interest.

Background: Background: Adjuvant androgen deprivation therapy (ADT) including a luteinising hormone releasing hormone analogue (LHRHA) is standard of care given before during and after radiotherapy for localised prostate cancer (PC) at high risk of recurrence. Enzalutamide is a new second generation androgen receptor (AR) inhibitor that is more potent and binds with a higher affinity to the AR than conventional non-steroidal anti-androgens (NSAA) and improves survival in metastatic castration-resistant PC. We hypothesise that the incorporation of enzalutamide in adjuvant ADT, given before, during and after radiation therapy for localised PC at high risk of recurrence, will further improve outcomes. Aim: To determine the effectiveness of enzalutamide as part of adjuvant ADT with a LHRHA in men planned for radiotherapy for localised PC at high risk of recurrence. Trial design: Open label, randomised, stratified, 2-arm, phase 3 intergroup trial Eligibility: Localised PC, high risk of recurrence, suitable for EBRT with curative intent Stratification: Gleason 8-10, T3-4, PSA >20, study site Endpoints: Overall survival (Primary), Cause-specific survival, PSA PFS, Clinical PFS, HRQOL, Adverse events, ICER Accrual: 800 participants. 2 yrs accrual + 5.5 years minimum f/up. 80% power to detect a 33% reduction in the hazard of death assuming a 5-year survival rate of 76% amongst controls. Participants will be randomised 1:1 to enzalutamisde 160mg daily for 24 months versus conventional NSAA for first 6 months. Background treatment for all participants: LHRHA for 24 months and EBRT (78Gy/39F) starting after week 16. Study assessments are at baseline, weeks 4, 12, 16, 20 and 24, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. Imaging with CT/MRI and bone scan at baseline and then as clinically indicated. Tertiary correlative objectives include the identification of prognostic / predictive biomarkers from archival tumour tissue, and from fasting bloods collected at baseline, 24 weeks, 5 years, and first evidence of progression. Email: enzarad@ctc.usyd.edu.au Website: http://www.anzup.org.au/ Disclosure: C. Sweeney: Consulting with honoraria to declare with Asetallas, Janssen and Sanofi; P. Nguyen: Consulted for Medivation (

Background: Bleomycin, Etoposide, Cisplatin (BEP) administered 3-weekly x 4 remains standard 1st line chemotherapy for intermediate- and poor-risk metastatic germ cell tumours (GCTs). High-dose chemotherapy and more complex regimens (eg VIP, T-BEP) have failed to improve cure rates and are more toxic. Accelerating regimens of standard chemotherapy by giving them 2-weekly rather than 3-weekly has improved cure rates in other cancers where more complex or higher-dose regimens failed. Aim: To determine if accelerated BEP is superior to standard BEP as 1st line chemotherapy for intermediate and poor risk metastatic GCTs. Trial design: Open-label, randomised, stratified 2-arm multicentre, 2 stage, phase 3 clinical trial. The primary endpoint for stage I of the trial (n = 150) is complete response rate, and for the complete trial (n = 500) is progression-free survival (PFS). A sample size of 150 and 500 patients gives >80% power to detect a 20% improvement in response rates and 7% absolute improvement in 2yr PFS, respectively. Participants: Males aged 16-45years with intermediate or poor-risk metastatic GCTs for 1st line chemotherapy. Planned expansion to include children aged 11+ and females. Regimen: Participants are randomised 1:1 to “standard BEP” or “accelerated BEP”: Timing of BEP accelerated vs standard Week 1 2 3 4 5 6 7 8 9 10 11 12 Standard EP EP EP EP B B B B B B B B B B B B Accelerated EP EP EP EP B B B B B B B B B B B B E-Etoposide 100mg/m2 D1-5; P-Cisplatin25mg/m2 D1-5; B-Bleomycin 30000 IU weekly; Peg G-CSF 6mg s/c given on D6 post EP in both arms Assessments: Weekly during BEP. Initial response assessment at 30-day safety assessment. Final response assessment at 6 months from randomisation or after all post-chemotherapy intervention is completed. Follow-up 3-monthly for 2 years from randomisation, then 6-monthly to 5 years, then annually. Tissue and blood collection for translational substudies Current status: In start-up phase or open to recruitment at 25 sites in Australia & New Zealand. International trial groups invited to participate. Email: p3bep@ctc.usyd.edu.au Webstite: http://www.anzup.org.au/ Disclosure: All authors have declared no conflicts of interest.