TPS282 Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. PRIME-RT tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in which is recruiting patients with metastatic disease. After opening in January 2021, the four patients completed the safety run in and the main trial commenced in March 2022. The trial is currently open across 5 UK sites. Up to date recruitment details will be provided at the time of presentation but at the time of writing this is ahead of target. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. Furthermore, on treatment biospecimen collection is also feasible across multiple sites. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Core funding (Glasgow CRUK CTU) and trial-specific funding (Astrazeneca). Clinical trial: NCT04621370; ISRCTN18138369. Clinical trial information: ISRCTN18138369 .

Background: Venous access devices are used for patients receiving long-term chemotherapy. These include centrally inserted tunnelled catheters or Hickman-type devices (Hickman), peripherally inserted central catheters (PICCs) and centrally inserted totally implantable venous access devices (PORTs). Objectives: To evaluate the clinical effectiveness, safety, cost-effectiveness and acceptability of these devices for the central delivery of chemotherapy. Design: An open, multicentre, randomised controlled trial to inform three comparisons: (1) peripherally inserted central catheters versus Hickman, (2) PORTs versus Hickman and (3) PORTs versus peripherally inserted central catheters. Pre-trial and post-trial qualitative research and economic evaluation were also conducted. Setting: This took place in 18 UK oncology centres. Participants: Adult patients (aged ≥ 18 years) receiving chemotherapy (≥ 12 weeks) for either a solid or a haematological malignancy were randomised via minimisation. Interventions: Hickman, peripherally inserted central catheters and PORTs. Primary outcome: A composite of infection (laboratory confirmed, suspected catheter related and exit site infection), mechanical failure, venous thrombosis, pulmonary embolism, inability to aspirate blood and other complications in the intention-to-treat population. Results: Overall, 1061 participants were recruited to inform three comparisons. First, for the comparison of peripherally inserted central catheters (n = 212) with Hickman (n = 212), it could not be concluded that peripherally inserted central catheters were significantly non-inferior to Hickman in terms of complication rate (odds ratio 1.15, 95% confidence interval 0.78 to 1.71). The use of peripherally inserted central catheters compared with Hickman was associated with a substantially lower cost (–£1553) and a small decrement in quality-adjusted life-years gained (–0.009). Second, for the comparison of PORTs (n = 253) with Hickman (n = 303), PORTs were found to be statistically significantly superior to Hickman in terms of complication rate (odds ratio 0.54, 95% confidence interval 0.37 to 0.77). PORTs were found to dominate Hickman with lower costs (–£45) and greater quality-adjusted life-years gained (0.004). This was alongside a lower complications rate (difference of 14%); the incremental cost per complication averted was £1.36. Third, for the comparison of PORTs (n = 147) with peripherally inserted central catheters (n = 199), PORTs were found to be statistically significantly superior to peripherally inserted central catheters in terms of complication rate (odds ratio 0.52, 95% confidence interval 0.33 to 0.83). PORTs were associated with an incremental cost of £2706 when compared with peripherally inserted central catheters and a decrement in quality-adjusted life-years gained (–0.018) PORTs are dominated by peripherally inserted central catheters: alongside a lower complications rate (difference of 15%), the incremental cost per complication averted was £104. The qualitative work showed that attitudes towards all three devices were positive, with patients viewing their central venous access device as part of their treatment and recovery. PORTs were perceived to offer unique psychological benefits, including a greater sense of freedom and less intrusion in the context of personal relationships. The main limitation was the lack of adequate power (54%) in the non-inferiority comparison between peripherally inserted central catheters and Hickman. Conclusions: In the delivery of long-term chemotherapy, peripherally inserted central catheters should be considered a cost-effective option when compared with Hickman. There were significant clinical benefits when comparing PORTs with Hickman and with peripherally inserted central catheters. The health economic benefits were less clear from the perspective of incremental cost per quality-adjusted life-years gained. However, dependent on the willingness to pay, PORTs may be considered to be cost-effective from the perspective of complications averted. Future work: The deliverability of a PORTs service merits further study to understand the barriers to and methods of improving the service. Trial registration: This trial is registered as ISRCTN44504648. Funding: This project was funded by the National Institute for Health Research (NHIR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 47. See the NIHR Journals Library website for further project information.

Background Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. Methods PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m 2 oxaliplatin, 350 mg folinic acid and 400 mg/m 2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m 2 5-FU infusion over 46–48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m 2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. Discussion PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020)

Background Hickman-type tunnelled catheters (Hickman), peripherally inserted central catheters (PICCs), and totally implanted ports (PORTs) are used to deliver systemic anticancer treatment (SACT) via a central vein. We aimed to compare complication rates and costs of the three devices to establish acceptability, clinical effectiveness, and cost-effectiveness of the devices for patients receiving SACT. Methods We did an open-label, multicentre, randomised controlled trial (Cancer and Venous Access [CAVA]) of three central venous access devices: PICCs versus Hickman (non-inferiority; 10% margin); PORTs versus Hickman (superiority; 15% margin); and PORTs versus PICCs (superiority; 15% margin). Adults (aged >= 18 years) receiving SACT (>= 12 weeks) for solid or haematological malignancy from 18 oncology units in the UK were included. Four randomisation options were available: Hickman versus PICCs versus PORTs (2:2:1), PICCs versus Hickman (1:1), PORTs versus Hickman (1:1), and PORTs versus PICCs (1:1). Randomisation was done using a minimisation algorithm stratifying by centre, body-mass index, type of cancer, device history, and treatment mode. The primary outcome was complication rate (composite of infection, venous thrombosis, pulmonary embolus, inability to aspirate blood, mechanical failure, and other) assessed until device removal, withdrawal from study, or 1-year follow-up. This study is registered with ISRCTN, ISRCTN44504648. Findings Between Nov 8, 2013, and Feb 28, 2018, of 2714 individuals screened for eligibility, 1061 were enrolled and randomly assigned, contributing to the relevant comparison or comparisons (PICC vs Hickman n=424, 212 [50%] on PICC and 212 [50%] on Hickman; PORT vs Hickman n=556, 253 [46%] on PORT and 303 [54%] on Hickman; and PORT vs PICC n=346, 147 [42%] on PORT and 199 [58%] on PICC). Similar complication rates were observed for PICCs (110 [52%] of 212) and Hickman (103 [49%] of 212). Although the observed difference was less than 10%, non-inferiority of PICCs was not confirmed (odds ratio [OR] 1.15 [95% CI 0.78-1.71]) potentially due to inadequate power. PORTs were superior to Hickman with a complication rate of 29% (73 of 253) versus 43% (131 of 303; OR 0.54 [95% CI 0.37-0.77]). PORTs were superior to PICCs with a complication rate of 32% (47 of 147) versus 47% (93 of 199; OR 0.52 [0.33-0.83]). Interpretation For most patients receiving SACT, PORTs are more effective and safer than both Hickman and PICCs. Our findings suggest that most patients receiving SACT for solid tumours should receive a PORT within the UK National Health Service. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

2018 Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (O) has radio and chemosensitizing properties in GBM models. Clinical development of PARP inhibitor combinations has been restricted by exacerbation of hematological toxicity and acute radiation toxicity. We studied pharmacokinetics (PK), safety and toxicity of O with RT and/or TMZ in three phase I studies. Methods: OPARATIC determined PK of O (AZ tablet formulation) in core and margins of recurrent GBM and maximum tolerated dose (MTD) of O with 42 day cycles of daily TMZ. PARADIGM determined recommended phase II dose (RP2D) of O with 40 Gy 15 fractions of radiotherapy in newly diagnosed patients aged > 70. PARADIGM-2 comprises two phase I studies of O+RT (60 Gy 30#, MGMT unmethylated) or O+RT+TMZ (MGMT methylated) in newly diagnosed patients aged < 70. Results: OPARATIC: 48 patients recruited; 27 underwent surgery, 36 receiving O/TMZ were evaluable. O detected in 71/75 tumor core specimens (27 patients); mean conc. 588nM (97-1374nM), and 27/28 tumor margin specimens (10 patients); mean conc. 500nM (97-1237 nM). Myelosuppression necessitated intermittent O dosing. MTD defined as O 150 mg (OD) days 1-3 weekly plus TMZ 75 mg/m2 daily. For 36 evaluable patients receiving 0/TMZ, progression-free survival at 6 months was 39%. PARADIGM: 16 patients (median age 72) treated in four O dose cohorts. One DLT (agitation grade 3) recorded (cohort 3, 100 mg BID). RP2D of O +40Gy 5# in elderly GBM was 200 mg BID daily. Median overall survival 10.3 months (80% CI: 6.3 – 11.7 months) at 12.9 months median follow up. PARADIGM-2: 29 patients screened, 14 commenced study treatment. Three MGMT unmethylated patients completed cohort 1 (50 mg QID) with no DLTs and 4 recruited to cohort 2 (100 mg QID) with no DLTs to date. Seven MGMT methylated patients recruited to cohort 1 (100 mg x1 per week); 1 DLT reported to date (low platelets). Conclusions: O penetrates core and margins of recurrent GBM. Combination with TMZ requires intermittent dosing but is safe and well tolerated. Combination with radiotherapy is extremely well tolerated and randomized phase II evaluation is underway. Clinical trial information: NCT01390571.

Olaparib, a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP), has radiosensitising properties in pre-clinical GBM models. Because radiopotentiation is observed only in proliferating cells, we hypothesised that olaparib would enhance tumour control without exacerbating normal brain toxicity in GBM patients receiving radiotherapy. Having shown that olaparib penetrates GBM at radiosensitising concentrations, we studied its safety and toxicity in combination with short-course radiotherapy in GBM patients ineligible for radical chemoradiation. Patients aged ≥70 (WHO PS 0–1) or <70 (PS 2) with histologically confirmed GBM received oral olaparib commencing three days before and continuing throughout radiotherapy (40 Gray in 15 fractions) and for four weeks afterwards. Olaparib dose was escalated in a 3 + 3 cohort design. 16 patients (9 male, 7 female) were treated within four olaparib dose cohorts. Median age was 72 (range 44–78); four patients had WHO PS 0, eight PS 1 and four PS 2. Cohort 3 was expanded to six evaluable patients because one patient experienced the only dose-limiting toxicity observed in the study (agitation grade 3, CTCAE v.4). Serious adverse events were experienced by eight patients, of which only one (the DLT) was a serious adverse reaction. The recommended dose of olaparib for phase II testing in combination with short-course radiotherapy was determined to be 200 mg twice daily. As predicted by pre-clinical data, olaparib is extremely well tolerated in combination with short-course radiotherapy in elderly and poorer PS patients with newly diagnosed GBM. The recommended phase II dose of 200 mg twice daily is significantly higher than has been deliverable to date in extracranial tumour sites in which acutely responding, rapidly proliferating normal tissues were within the irradiated volume. A randomised double-blind phase II study of radiotherapy plus olaparib versus radiotherapy plus placebo is underway in patients aged ≥65 with MGMT unmethylated GBM.