A collection of research papers published by the staff of The Christie NHS Foundation Trust between 1999 to present day. The collection is intended to back date all publications published since 1999. Older papers may be submitted by request to the Kostoris Library.

 

Recent Submissions

  • Unified classification and risk-stratification in Acute Myeloid Leukemia

    Tazi, Y.; Ossa, J. A.; Zhou, Y. Y.; Bernard, E.; Thomas, I.; Gilkes, A.; Freeman, S.; Pradat, Y.; Johnson, S.; Hills, R.; et al. (2022)
    Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.
  • RATIONALE-306: Randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC)

    Yoon, H.; Kato, K.; Raymond, E.; Hubner, Richard A; Shu, Y.; Pan, Y.; Jiang, Y.; Zhang, J.; Park, S.; Kojima, T.; et al. (2022)
    Background: Tislelizumab, an anti-programmed cell death protein 1 antibody, has demonstrated a survival benefit as second-line treatment in ESCC. Here, we report interim analysis (IA) data from the phase 3 RATIONALE-306 study, which evaluated the efficacy and safety of tislelizumab plus chemotherapy vs placebo plus chemo- therapy in patients with advanced or metastatic ESCC in the first-line setting. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Patients were randomized (1:1) to receive tislelizumab 200 mg (Arm A) or placebo (Arm B) intravenously once every three weeks, both in combination with investigator-chosen chemotherapy (ICC; platinum [cisplatin or oxaliplatin] and fluo- ropyrimidine [capecitabine or 5-FU] or platinum and paclitaxel) until disease pro- gression per RECIST v1.1, intolerable toxicity, or withdrawal. Randomization was stratified by geographic region, prior definitive therapy and ICC. The primary endpoint was overall survival (OS) in the intent-to-treat (ITT) population. Hierarchical sequentially-tested secondary endpoints were progression-free survival (PFS), objec- tive response rate (ORR) by the investigator, OS in the PD-L1 score ≥10% subgroup, and health-related quality of life. Other secondary endpoints included duration of response (DoR) by the investigator, and safety. Results: Of 649 patients enrolled from 16 countries/4 regions (74.9% and 25.1% from Asia and non-Asian countries [Europe, Oceania, and North America]), 326 and 323 patients were randomized to Arms A and B, respectively (ITT population). At data cutoff (28/02/2022), median follow-up was 16.3 and 9.8 months in Arms A and B, respectively. The study met its primary endpoint at IA by demonstrating statistically significant improvement in OS in Arm A vs Arm B (median OS: 17.3 vs 10.6 months; HR 0.66 [95% CI 0.54, 0.80], p<0.0001). OS improvement was consistently observed across prespecified subgroups including ICC option, region, and PD-L1 expression status. In patients with PD-L1 score ≥10%, Arm A also demonstrated significant improvement in OS vs Arm B (median OS: 16.8 vs 10.0 months, HR 0.61 [95% CI 0.44, 0.85], p=0.0017). A significant improvement in PFS was observed in Arm A vs Arm B (median PFS: 7.3 vs 5.6 months; HR 0.62 [95% CI 0.52, 0.75], p<0.0001). Arm A was associated with a higher ORR (63.5% vs 42.4%, odds ratio 2.38 [95% CI 1.73, 3.27], p<0.0001) and more durable response (median DoR: 7.1 [95% CI 6.1, 8.1] vs 5.7 months [95% CI 4.4, 7.1]) than Arm B. Overall, similar proportions of patients in Arms A and B had ≥1 treatment-related treatment-emergent adverse event (TRAE; 96.6% and 96.3%), ≥Grade 3 TRAEs (66.7% vs 64.5%), and TRAEs leading to death (1.9% vs 1.2%), respectively. Serious TRAEs occurred in 28.7% vs 19.3%, and treatment- emergent AEs leading to discontinuation occurred in 31.8% vs 22.4% in Arms A vs B. No new safety signal for tislelizumab was observed. Conclusions: Tislelizumab plus chemotherapy as first-line treatment demonstrated a statistically significant and clinically meaningful improvement in OS over placebo plus chemotherapy in patients with advanced or metastatic ESCC, with a manageable safety profile.
  • Outcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study

    He, A.; Valle, Juan W; Lee, C.; Ikeda, M.; Potemski, P.; Morizane, C.; Cundom, J.; Tougeron, D.; Dayyani, F.; Rokutanda, N.; et al. (2022)
    Background: The double-blind, phase 3 TOPAZ-1 study (NCT03875235) evaluated the efficacy and safety of durvalumab plus gemcitabine and cisplatin (GemCis) as first-line treatment for patients with advanced biliary tract cancer (BTC; Oh D-Y et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Durvalumab plus GemCis significantly improved overall survival (OS) versus placebo plus GemCis and represents a potential new first- line treatment option. In BTC, primary tumour location (intrahepatic or extrahepatic cholangiocarcinoma [IHCC/EHCC], or gallbladder cancer [GBC]) may impact risk fac- tors, prognoses, and response to treatment. Methods: The aim of this exploratory subgroup analysis of TOPAZ-1 was to assess efficacy outcomes, OS, progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) per RECIST v1.1, by primary tumour location in pa- tients receiving durvalumab versus placebo. Patients with BTC were randomised 1:1 to receive durvalumab (1500 mg) or placebo on Day 1 Q3W, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and 8 Q3W, for up to 8 cycles, followed by durvalumab or placebo monotherapy until disease progression, unacceptable toxicity or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (IHCC vs EHCC vs GBC). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for OS and PFS using a Cox proportional hazards model, and odds ratios (ORs) and 95% CIs for ORR were calculated using the Cochran-Mantel Haenszel test. Results: Patient numbers with IHCC, EHCC and GBC were balanced between treatment arms; more patients had IHCC than EHCC or GBC (durvalumab: n¼190, n¼66, n¼85; placebo: n¼193, n¼65, n¼86, respectively). HRs for OS favoured durvalumab: HR was 0.76 (95% CI, 0.58-0.98) for IHCC, 0.76 (95% CI, 0.49-1.19) for EHCC, and 0.94 (95% CI, 0.65-1.37) for GBC. To aid in understanding the higher HR in GBC, regional analysis was performed: the OS HR for GBC in Asia was 0.82 (95% CI, 0.48-1.40) and in Europe plus North America (non-Asian countries minus South America) was 0.78 (95% CI, 0.44-1.37). PFS HR was 0.79 (95% CI, 0.64-0.99) for IHCC, 0.52 (95% CI, 0.35-0.78) for EHCC, and 0.90 (95% CI, 0.65-1.24) for GBC. ORR favoured durvalumab in IHCC (24.7% vs 15.5%; OR, 1.79; 95% CI, 1.07-2.97), EHCC (28.8% vs 15.6%; OR, 2.18; 95% CI, 0.92-5.16) and GBC (29.4% vs 27.9%; OR, 1.08; 95% CI, 0.55-2.09). Percentages of responders with a DoR of at least 9 and 12 months were higher with durvalumab versus placebo for all tumour locations (9-month: IHCC 28.3% vs 24.0%, EHCC 43.3% vs 23.3%, GBC 33.2% vs 27.5%; 12-month: IHCC 18.9% vs 12.0%, EHCC 43.3% vs 23.3%, GBC 27.6% vs 16.5%). Conclusions: In TOPAZ-1, the addition of durvalumab to GemCis appeared to improve efficacy outcomes (not formally tested for subgroup comparisons) for patients with IHCC, EHCC and GBC. Though the magnitude of efficacy improvement varied slightly between primary tumour locations, the benefit of durvalumab was observed consistently. These findings support durvalumab plus GemCis as a treatment option for BTC, irrespective of primary tumour location.
  • Prevention Of Breast and Endometrial cancer using Total Diet Replacement (PROBE-TDR) trial: protocol for a randomised controlled trial

    Clarke, Helen; Harvie, M.; Lombardelli, C.; Krizak, S.; Sellers, K.; Harrison, Hannah; Lim, Y. Y.; Parkin, C.; Patel, S.; Issa, B. G.; et al. (2022)
    Introduction Obesity and overweight are strong potentially modifiable risk factors for postmenopausal breast and endometrial cancer. Bariatric surgery can achieve considerable weight loss and risk reduction of weight-related cancer but is unlikely to be a feasible cancer prevention strategy. Total diet replacement (TDR) can also lead to significant weight reduction. This study aims to examine the cellular and molecular changes in breast and endometrial tissue in high-risk women following TDR-induced weight loss, as well as longer-term adherence to a 12-month TDR weight loss intervention. Methods and analysis PROBE-TDR (PRevention Of Breast and Endometrial cancer using Total Diet Replacement) is a prospective, non-blinded, randomised controlled trial of 47 women at increased risk of breast and/or endometrial cancer. Randomisation is 2:1 to either an immediate 12-month TDR weight loss programme (n=31) or delayed dietary intervention (control) (n=16). The TDR programme includes an initial 12-week period of TDR (850 kcal/ day) followed by a 40-week food-based diet, based on the nutritional principles of a Mediterranean diet, as either continued weight loss (~1500 kcal/ day) or weight loss maintenance (~2000 kcal/day). Menstrual phase-matched biopsies of the breast and endometrium will be assessed at baseline and at the end of the 12-week TDR in the immediate diet group, compared with women randomised to the control group following their usual diet. The trial will also assess longer-term adherence and weight loss success across the 12-month programme in both the immediate and control groups. Ethics and dissemination Approval for this study has been obtained from the Health Research Authority and Health and Care Research Wales (approval 20/ NW/0095). Results will be published in peer-reviewed journals, presented at conferences and shared with trial participants.
  • Real-world utility of full staging with 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) in addition to standard imaging in patients with non-metastatic non-resectable pancreatic ductal adenocarcinoma (PDAC)

    Wheatley, Roseanna; McNamara, Mairead G; Gleeson, J.; Hubner, Richard A; Manoharan, Prakash; Valle, Juan W; Lamarca, Angela; The University of Manchester/The Christie National Health Service Foundation Trust, Manchester, (2022)
    Background: Previous studies support 18FDG-PET utility for staging of patients (pts) with non-metastatic PDAC (M0-PDAC); while its use has been adopted in some countries (i.e. NICE guidelines in the United Kingdom), its use in this setting is vari- able, especially in relation to non-resectable disease. This study explored the utility of performing 18FDG-PET in real-world clinical practice for pts with a working diagnosis of non-resectable M0-PDAC based on cross-sectional imaging. Methods: Notes from consecutive pts with PDAC seen at The Christie NHS Foundation Trust (01/07/2018-02/02/2022; Audit Committee approval: 2020/2654) were reviewed. Eligible pts were those with a diagnosis of non-resectable M0-PDAC (with primary tumour in situ) who underwent full staging with an 18FDG-PET (standard practice for all pts during time period explored). The primary end-point was the percentage of pts identified to have distant metastases on 18FDG-PET. Secondary objectives: factors associated with presence of distant metastases, and impact of 18FDG-PET findings on patient outcomes (overall survival (OS); defined as the time from when pts were first seen for consideration of systemic therapies to time of death or last follow-up). Statistical analysis: STATA v.17, including logistic and Cox Regression. Results: A total of 1637 pts were screened; of these, 56 were eligible. Thirty pts (53.37%) were male; median age: 72 years (range 34-83); the majority had primary tumour located in the head (n¼40, 71.43%), ECOG performance Status (ECOG PS) 0/1 (n¼48, 85.71%) with none/mild comorbidities (37 pts, 66.07%; 22 pts (39.29%) had diabetes) and treatment naive (52 pts, 92.86%; 4 pts had received prior chemo- therapy (all FOLFIRINOX)); stage prior to 18FDG-PET: T4 (39 patients; 69.64%), regional lymph node disease (25 patients; 44.64%), M0 (56 patients; 100%). In 19 patients (33.93%) the 18FDG-PET identified presence of metastatic disease; with incidental findings in 12 patients (21.50%) (incidental findings were identified in 7 patients without evidence of distant metastatic disease in 18FDG-PET). Logistic regression identified T4 stage (vs T1/2/3 stage) as the only factor associate with higher risk of metastatic disease in 18FDG-PET (46.15% vs 5.88%; Odds Ration (OR) 13.71 (95% 1.65-113.81); p-value 0.015). At time of analysis 31 patients (55.36%) had died; median follow up was 8.54 months (95% CI 6.10-10.64). Estimated median OS for the whole population was 12.53 months (95% CI 9.16-14.74). Patients identified to have presence of distant metastases in 18FDG-PET had a shorter OS (8.07 months (95% CI 4.23-16.53) vs 14.38 (95% CI 11.01-19.17)); prognostic impact was confirmed in multivariable Cox Regression (HR 3.48 (95% CI 1.76-12.04); p-value 0.002) adjusted to other prognostic factors (PS (HR 3.48 (95% CI 1.57-7.71); p-value 0.002)). Conclusions: 18FDG-PET allows identification of otherwise occult metastatic disease in a third of the pts (this rate is higher for patients with stage T4 disease). Staging with 18FDG-PET in pts with non-resectable M0-PDAC should be considered standard of care to allow access to appropriate standard-of-care treatment options and recruit- ment into clinical trials. In addition, its prognostic implications could enable optimi- sation of patient information given, management of expectations and future care planning.
  • Clinical role of tumour markers in advanced biliary cancers (ABC) treated with second-line active-symptom-control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC plus mFOLFOX) in the randomised phase III, multi-centre, open-label ABC-06 trial

    Lamarca, Angela; Palmer, D.; Wasan, H.; Ross, P.; Ma, Y. T.; Arora, A.; Falk, S.; Gillmore, R.; Wadsley, J.; Patel, K.; et al. (2022)
    Background: The ABC-06 clinical trial stablished ASC+mFOLFOX as the standard of care treatment after Cisplatin and Gemcitabine (CisGem) for ABC. Methods: Within the ABC-06 study, patients (pts) diagnosed with ABC (chol- angiocarcinoma, gallbladder or ampullary cancer) with progression after CisGem were randomised (1:1) to ASC+mFOLFOX or ASC. Tumour markers (CA19.9, CEA and CA125), were scheduled at baseline (BSL) and at every follow-up visit. This post-hoc analysis explored if changes (stable/reducing vs increasing) of Ca19.9 at week 4 from initiation of ASC+mFOLFOX was associated with radiological progression-free survival (PFS). Secondary end-points included impact of raised BSL Ca19.9 (defined as x1.5 ULN) and chemotherapy-induced changes on overall survival (OS). CEA and CA125 were also analysed. Results: Out 162 pts randomised, BSL Ca19.9 data was available for 135 pts. Paired BSL and week-4 Ca19.9 data was available for 37 pts in the ASC+mFOLFOX arm: Ca19.9 was stable/reducing in 17 (45.9%) and increasing in 20 pts (54.1%). Stable/ reducing Ca19.9 showed a numerically longer median radiological PFS (4.3 months (m) vs 3.3m) but differences did not reach statistical significance (HR 1.08 (95% CI 0.55-2.14); p¼0.81). When restricted to patients with raised BSL Ca19.9 (23 pts), impact on PFS was more marked (5.7m vs 3.2m), but remained non-significant (HR 1.68 (95% CI 0.70-4.01); p¼0.23). Stable/reducing Ca19.9 at week 4 did not impact significantly on OS (p¼0.56 (regardless of BSL Ca19.9 level; 37 pts); p¼0.84 (if raised BSL Ca19.9; 23 pts)). Raised BSL Ca19.9 was associated both with shorter unadjusted clinical median PFS (3.2m vs 5.0m; HR 1.53 (95% CI 1.05-2.23); p¼0.027) and un- adjusted OS (4.4m vs 6.4m; HR 1.97 (95% CI 1.33-2.93); p When Cox Regression model (120 pts) for OS exploring the prognostic roles of raised BSL Ca19.9, CEA and CA125 was adjusted for pre-defined stratification factors (platinum sensitivity, albumin, and stage) and randomised trial arm, each raised tumour marker had an independent impact (HR 1.56 (95% CI 1.03 to 2.35); p¼0.03 / HR 1.60 (95% CI 1,06 to 2.43) p¼0.026 / HR 1.70 (95% CI 1.13 to 2.56); p¼0.011 for Ca19.9, CEA and CA125, respectively). Unadjusted median OS was 8.9m if all tumour markers at BSL were non- raised, and 7.0m, 4.0m, 3.2m in the event of having 1, 2 or 3 raised BSL tumour markers. Conclusions: For ABC patients treated with second-line ASC+mFOLFOX, utility of Ca19.9 measured at week-4 after chemotherapy initiation is limited; raised BSL Ca19.9, CEA and CA125 have independent prognostic roles and future studies may need to consider these (individually or pooled) as stratification factors.
  • Impact of an educational activity on the competence of oncologists and gastroenterologists regarding the application of molecular-guided therapies for the treatment of advanced cholangiocarcinoma

    Johnson, B.; Peters, K.; Scot-Smith, C.; Lucero, K.; Lamarca, Angela; Medscape Oncology, Amsterdam, Netherlands (2022)
    Background: Cholangiocarcinoma (CCA) is a rare, aggressive cancer of the biliary tract with patients often having a poor prognosis and complex genetic heterogeneity. Following recent approvals of targeted therapies for the treatment of advanced CCA, the objective of this online, continuing education activity was to determine whether improvements in competence could be made regarding the identification of patients and application of molecularly guided therapy to advanced CCA through the use of interactive and engaging patient cases. Methods: Oncologists and gastroenterologists participated in an online, interactive clinical case based educational activity focusing on the identification of patients for molecular guided therapy, clinical decision making and management while on therapy for patients with advanced cholangiocarcinoma. Educational effect was assessed using a repeated-pair design with pre-/post-assessment. 3 multiple choice questions assessed competence, and 1 question rated on a Likert-type scale assessed confi- dence. Data were collected from 11/01/21 to 02/03/22. A paired samples t-test was conducted for significance testing on overall average number of correct responses and for confidence rating, and a McNemar’s test was conducted at the question level (5% significance level, P < .05). Improvements were defined as a learner answering the question correctly in the post-assessment after they previously answered it incor- rectly in pre-assessment. Reinforcements were when the learner answered the question correctly in both instances of assessment. Results: The responses of 42 oncologists and 44 gastroenterologists, who answered all questions as part of the pre- and post-activity assessment during the study period were included in the analysis. Overall, 71% and 70% of oncologists and gastroenterologists, respectively, improved their competence across the activity. Specific areas of improvement included (all P < 0.001): 26% and 32% of oncologists and gastroenter- ologists, respectively, improved and 67% and 66% of oncologists and gastroenterolo- gists, respectively, reinforced their competence regarding the identification of patients eligible for molecular targeted therapy. Regarding the application of molecularly guided therapy in routine practice, a relative change of 53% in competence was observed for oncologists and 61% for gastroenterologists. As a result of the education, 55% of the oncologists and 64% of gastroenterologists had a measurable improvement in confi- dence in their ability to apply molecular testing results to treatment selection in pa- tients with CCA (P < 0.001 for both specialties), which led to an average positive confidence shift of 82% for oncologists and 105% for gastroenterologists. Conclusions: This study demonstrated the effectiveness of an online, interactive, case-based educational activity on improving the competence and confidence of oncologists and gastroenterologists regarding the application of molecular targeted therapy to clinical cases with advanced CCA. It will be critical to focus future edu- cation on building upon these improvements and increasing exposure of physicians to more opportunities of clinical simulation.
  • Quality of life (QoL)-based end-points for patients with advanced pancreatic ductal adenocarcinoma (aPDAC): Results from the PanDA prospective observational study

    Lamarca, Angela; Carnie, Lindsay E; Shah, Dinakshi; Vaughan, K.; Kapacee, Zainul Abedin; McCallum, L.; Abraham, Marc; Backen, Alison C; Gillespie, Loraine; McNamara, Mairead G; et al. (2022)
    Background: Adequate design of clinical trials using QoL-based primary-end points to assess benefit derived from supportive interventions such as exercise, nutrition or complementary therapies is challenging in PDAC due to a lack of available data describing baseline QoL and changes over time for this patient population. Methods: PanDA was a prospective observational study of prevalence, assessment and treatment of pancreatic exocrine insufficiency in patients with aPDAC (NCT03616431). QoL data using the EORTC QlQ-C30 and QLQ-PAN26 questionnaires were collected for the follow-up cohort at baseline (BSL), week6 (W6) and month3 (M3). This post-hoc analysis included patients with aPDAC and explored the mean and standard deviation (SD) of the Physical Functioning Scale (PhFS) at BSL, W6, M3) and mean (SD) intra-patient changes over time (W6-BSL and M3-BSL). Subgroup analysis by stage (locally-advanced vs metastatic) was also performed. Percentage of patients evaluable at each time point was reported. Descriptive statistical analysis was per- formed (Stata v.17). Results: Of 37 patients recruited into the follow-up cohort, 32 met eligibility criteria for this post hoc analysis. Thirty (93.8%), 17 (53.1%; all had paired BSL data) and 13 (40.6%; all had paired BSL data) patients were evaluable with PhFS data available at BSL, W6 and M3, respectively. PhFS (mean (SD); number of observations) did not vary over time when all patients were analysed together (BSL: 76.17(26.46);30) (W6: 79.18(12.74);17) (M3: 74.46(16.76);13). Intra-patient mean changes at W6 (-6.59(15.13);17) or M3 (-5.46(24.82);13). Subgroup analysis identified that changes in W6 were more marked in patients with metastatic disease (-12.14(15.54);7) compared to locally advanced (-2.70(14.32);10). Conclusions: Changes on PhFS over time were likely impacted by selection bias. Intra- patient mean changes at W6 or M3 seemed more reliable to be utilised as primary- end point and sample size calculation in future clinical trials. Subgroup analysis identified that changes in W6 were more marked in patients with metastatic Intra- patient changes rather than pooled results may be more reliable when designing clinical trials with QoL-based primary end-points in aPDAC. W6 assessment may be most informative, as waiting until M3 may compromise the power of the study due to significant drop out.
  • Outcomes by disease status in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study

    Okusaka, T.; Kitano, M.; Chen, M.; Chen, J.; Ostwal, V.; McNamara, Mairead G; Breder, V.; Petrova, M.; Buchschacher, G.; Rokutanda, N.; et al. (2022)
    Background: TOPAZ-1 (NCT03875235) was a randomised, double-blind, global, phase 3 study evaluating the efficacy and safety of durvalumab plus gemcitabine and cisplatin (durvalumab) as first-line treatment for patients with advanced biliary tract cancer (BTC; Oh D-Y, et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Durvalumab significantly improved overall survival (OS) versus placebo plus gemcitabine and cisplatin (placebo) and represents a potential new treatment option for patients with advanced BTC. In BTC, disease status at baseline (initially unresectable vs recurrent [>6 months after surgery with curative intent or >6 months after adjuvant therapy]) may impact response to treatment. Methods: The aim of this exploratory subgroup analysis of TOPAZ-1 was to assess efficacy outcomes by disease status at baseline in patients receiving durvalumab versus placebo. Patients with BTC were randomised 1:1 to receive durvalumab (1500 mg) or placebo on Day 1 Q3W, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/ m2) on Day 1 and 8 Q3W, for up to 8 cycles, followed by durvalumab or placebo monotherapy until disease progression, unacceptable toxicity or other discontinua- tion criteria were met. Randomisation was stratified by disease status and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic chol- angiocarcinoma vs gallbladder cancer). Subgroup analysis of OS, progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) per RECIST v1.1 by disease status at baseline (initially unresectable or recurrent) was performed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for OS and PFS using a Cox proportional hazards model, and odds ratios (ORs) and 95% CIs for ORR were calculated using the Cochran-Mantel Haenszel test. Results: The study included more patients with initially unresectable than recurrent disease (durvalumab, n¼274 [80.4%] vs n¼67 [19.6%]; placebo, n¼279 [81.1%] vs n¼64 [18.6%]). HRs for OS favoured durvalumab for both initially unresectable (0.84; 95% CI, 0.69e1.03) and recurrent (0.56; 95% CI, 0.32e0.96) disease; HRs for PFS also favoured durvalumab in both subgroups (0.79; 95% CI 0.66e0.95 and 0.63; 95% CI 0.42e0.94, respectively). ORs for ORR favoured durvalumab for both initially unre- sectable (1.61; 95% CI, 1.06e2.45) and recurrent (1.52; 95% CI 0.73e3.18) disease. Median DoR for durvalumab versus placebo was 6.0 versus 5.1 months for initially unresectable, and 9.7 versus 7.9 months for recurrent disease. Percentage of re- sponders with a DoR of at least 9 and 12 months was numerically higher with dur- valumab versus placebo for both initially unresectable (9-month, 21.5% vs 20.3%; 12- month, 16.7% vs 10.7%) and recurrent (9 months, 58.8% vs 38.1%; 12 months, 48.1% vs 25.4%) disease. Conclusions: In TOPAZ-1, addition of durvalumab to GemCis improved efficacy out- comes both in patients with initially unresectable and patients with recurrent disease at baseline, though the relative benefit versus placebo appears greater for recurrent compared with initially unresectable disease. These findings support the use of dur- valumab plus GemCis as a potential new treatment option for patients with advanced BTC, irrespective of disease status.
  • EMERGE: A multi-centre, non-randomised, single-arm phase II study investigating domatinostat plus avelumab in patients with previously treated advanced mismatch repair-proficient oesophagogastric and colorectal adenocarcinoma

    Slater, S.; Cartwright, E.; Saffery, C.; Tran, A.; Smith, G.; Bacason, M.; Zhitkov, O.; Rana, I.; Johnston, E.; Sanna, I.; et al. (2022)
    Background: Mismatch repair proficient (MMRp) oesophagogastric (OG) and colo- rectal cancers (CRC) respond less frequently to checkpoint inhibition. Epigenetic modulation of tumours using HDAC inhibitors can increase the chance of response to immunotherapy. We previously reported dose escalation (EMERGE phase IIA) and the established recommended phase II dose (RP2D) of domatinostat (selective class I HDAC inhibitor) 200mg BID continuously plus avelumab 10mg/kg q2w. Methods: Patients with MMRp advanced OG and CRC who received at least one prior line of chemotherapy were enrolled in two cohorts. Patients were treated with a two- week domatinostat prime (orally) followed by combination domatinostat and avelu- mab from cycle 2 onwards. The trial was conducted using a Simon two-stage optimal design. The primary endpoint was best objective response rate (ORR) 6 months from initiation of combination treatment by RECIST 1.1. A secondary end point was disease control rate (DCR) during the same period. The total accrual target was 29 in the CRC cohort and 34 patients in the OG cohort, with interim analysis due to take place once 10 CRC patients and 9 OG patients had been evaluated for best ORR; 1 response and 2 responses were required in the respective cohorts to proceed to stage two. Results: 21 patients were recruited between January 2020 and October 2021. In the OG cohort 9 patients were treated. 56% patients had received 2 prior lines of systemic anti-cancer therapy (SACT). The median duration of treatment was 1.8 months (range: 0.9-12.8). The best ORR was 22.2% [95% CI: 2.8, 60.0] (one PR and one CR). The patient with PR had a combined positive score (CPS) of 9, whilst the CPS was unavailable for the patient with CR. At time of data cut off on 25th February 2022, both patients remained on treatment at cycles 28 and 16 respectively. The median CPS for the patients whose disease did not respond to treatment was 12 (range: 0- 26). In the CRC cohort, 12 patients were treated; of these, 2 did not receive avelumab and were non-evaluable. In the evaluable CRC population, 90% received 2 prior lines of SACT. No responses were observed. DCR was 30.0% [95% CI: 6.7, 65.2]. The median duration of treatment was 2 months (range: 1.3-9.0). The most common treatment related adverse events (TRAE) of any grade were fatigue (58%), anaemia (37%) and nausea (32%). There were no grade 3 TRAEs reported. Conclusions: For OG adenocarcinoma the ORR of 22.2% met the criteria to expand the stage two recruitment with a favourable safety profile. In CRC there was insuf- ficient signal to progress to stage two.
  • PROOF 301: A multicenter, open-label, randomized, phase 3 trial of infigratinib vs gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement

    Abou-Alfa, G.; Borbath, I.; Goyal, L.; Lamarca, Angela; Macarulla, T.; Oh, D.; Roychowdhury, S.; Sadeghi, S.; Shroff, R.; Soto, J.; et al. (2022)
    Background: First-line treatment options are limited for patients with advanced cholangiocarcinoma (CCA). Genetic alterations in the fibroblast growth factor receptor (FGFR) gene play an important role in CCA. FGFR gene fusions/rear- rangements are present in 10e16% of intrahepatic CCA and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is a potent, orally bioavailable, selective, ATP-competitive, small-molecule tyrosine kinase inhibitor of FGFRs that showed promising clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable locally advanced/ metastatic CCA with an FGFR2 gene fusion/rearrangement. The multicenter, open- label, randomized, controlled phase 3 PROOF 301 trial is evaluating infigratinib vs standard-of-care gemcitabine + cisplatin as first-line treatment for patients with advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/ rearrangement. Trial design: Approximately 300 patients 18 years of age with histologically or cytologically confirmed, advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement (confirmed by central laboratory) are randomized 2:1 to oral infigratinib 125 mg once daily for the first 21 days of a 28-day treatment cycle vs intravenous standard gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. Randomization will be stratified by unre- sectable locally advanced vs metastatic disease, geographic region, prior neo- adjuvant/adjuvant treatment vs none, and receipt of up to 1 cycle of gemcitabine- based chemotherapy for unresectable locally advanced/metastatic disease prior to randomization vs none. Treatment will continue until confirmed progressive dis- ease by blinded independent central review (BICR), intolerance, withdrawal of informed consent, or death. Patients on the gemcitabine + cisplatin arm who develop disease progression (confirmed by BICR) can cross-over to receive infi- gratinib. The primary endpoint is progression-free survival (PFS; RECIST v1.1; confirmed by BICR). Secondary endpoints include overall survival, PFS (investi- gator determined), overall response rate, best overall response, disease control rate, duration of response (BICR and investigator determined), and the type, frequency, and severity of adverse events (AEs) and serious AEs. PFS after sub- sequent therapy (PFS2), quality of life, pharmacokinetics and other exploratory genetic alterations/biomarkers will also be evaluated. Trial enrollment is ongoing in the US, EU, and APAC (including Australia). The data monitoring committee last reviewed the trial in December 2021.
  • Pre-surgical staging and surveillance after curative treatment for pancreatic ductal adenocarcinoma (PDAC): Survey of practice in the United Kingdom (UK)

    Lamarca, Angela; Roberts, K.; Graham, J.; Kocher, H.; Chang, D.; Ghaneh, P.; Jamieson, N.; Propper, D.; Bridgewater, J.; Ajithkumar, T.; et al. (2022)
    Background: Differences in pre-operative staging and surveillance after curative treatment for PDAC hamper interpretation of outcome data. Methods: This survey aimed to assess current practice and identify areas for improvement; it was circulated to members of the United Kingdom National Cancer Research Institute (NCRI) pancreatic cancer subgroup between 14/4-4/5 2021. Results: A total of 23 responses were collected (medical oncologist 52.2%, surgeon 26.1%, radiation oncologist 13.0%, other 8.7%); the majority were Consultants (91.3%) working in tertiary care institutions (86.9%) who attended PDAC tumour boards (90.9%). For staging prior to curative surgery, all responders used compu- terised tomography (CT) (100%), and 61.1% used routine 18FDG positron emission tomography (PET) (16.7% used it only in specific occasions); only 38.9% used routine liver magnetic resonance imaging (MRI). In terms of surveillance following curative treatment, practice varied widely: 64.7% of responders considered imaging, tumour marker and clinical follow-up as routine practice after curative treatment, while 29.4% undertook follow-up without imaging; 5.9% did not offer any form of surveillance. Frequency of follow-up was either 6-monthly (60.0%), 3-monthly (26.7%), or variable (13.3%) and lasted for 5 years (73.3%), 2 years (6.7%), 3 years (6.7%), or other (13.3%). Surveillance imaging performed was by CT scanning in all cases (46.7% as routine, 6.7% if not done previously, 6.7% on occasions); none of the responders used FDG-PET (0%) or liver-MRI (0%). During surveillance, tumour marker (CA 19.9) was tested 6-monthly (66.7%), 3-monthly (40.0%), or annually (26.7%). Most (62.5%) stated that routine follow-up after curative treatment should be performed, but that clear evidence determining the impact on patient’s outcome was required. Conclusions: Pre-surgical staging with 18FDG-PET is not yet routine. Surveillance after curative treatment varies between institutions, both in terms of investigations per- formed (if any) and duration. Further guidance is required to establish standardised practice.
  • Olaparib maintenance versus placebo monotherapy in patients with advanced non-small cell lung cancer (PIN): A multicentre, randomised, controlled, phase 2 trial

    Fennell, D. A.; Porter, C.; Lester, J.; Danson, S.; Blackhall, Fiona H; Nicolson, M.; Nixon, L.; Gardner, G.; White, A.; Griffiths, G.; et al. (2022)
    Background: Impaired double strand DNA repair by homologous repair deficiency (HRD) leads to sensitivity to poly ADP ribose polymerase (PARP) inhibition. Poly-ADP ribose polymerase (PARP) inhibitors target HRD to induce synthetic lethality and are used routinely in the treatment of BRCA1 mutated ovarian cancer in the platinum-sensitive maintenance setting. A subset of non-small cell lung cancers (NSCLCs) harbour impaired DNA double strand break repair. We therefore hypothesised that patients with metastatic non-small cell lung cancer exhibiting partial responses to platinum doublet-based chemotherapy, might enrich for impaired HRD, rendering these tumours more sensitive to inhibition of PARP inhibition by olaparib. Methods: The Olaparib Maintenance versus Placebo Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer trial (PIN) was a multicentre double-blind placebo controlled randomised phase II screening trial. This study was conducted at 23 investigative hospital sites in the UK. Patients had advanced (stage IIIB/IV) squamous (Sq) or non-squamous (NSq) NSCLC, and had to be chemo-naive, European Cooperative Oncology Group (ECOG) performance status 0-1. Prior immunotherapy with a PD1 or PDL1 inhibitor was allowed. Patients could be registered for PIN prior to (stage 1), or after (stage 2) initiation of induction chemotherapy. If any tumour shrinkage was observed (any shrinkage of RECIST target lesions), following a minimum of 3 cycles of platinum doublet chemotherapy, patients were randomised 1:1 using a centralised online system, to either olaparib (300 mg twice daily by mouth in 21-day cycles) or placebo, which was continued until disease progression, or unacceptable toxicity. Intention to treat (ITT) analyses of the primary endpoint included all randomised participants. Per protocol (PP) safety analysis included all participants who received at least one dose of study drug. Primary endpoint was progression-free survival (PFS), with a one-sided p-value of 0.2 to demonstrate statistical significance. Hazard ratios (HR) for PFS were both unadjusted and adjusted for the randomisation balancing factors (smoking status and histology). The trial was registered with ClinicalTrials.gov (NCT01788332) and EudraCT (2012-003383-51). Findings: A total of 940 patients were assessed for stage 1 eligibility of whom 263 were registered between Feb 24, 2014 and Nov 7, 2017. 194 patients were excluded prior to stage 2 (no tumour shrinkage or unevaluable) and 70 were randomised; 32 (46%) to Olaparib and 38 (54%) to placebo. 4% (3/70) of patients randomised had a CR and 96% (67/70) had a PR (or other evidence of tumour response/mixed stable) during induction therapy. A total of 36 patients were registered in stage 2 only, i.e., post induction therapy. Intention to treat (ITT) unadjusted analysis showed a PFS hazard ratio (HR) of 0.83 (one-sided 80% CI upper limit 1.03, one-sided unadjusted log rank test p-value=0.23). ITT Cox-adjusted model showed a HR 0.73 (one-sided 80% CI upper limit 0.91, one sided p-value 0.11). Adverse events were reported in 31/32 subjects (97%) in the olaparib arm and 38/38 (100%) in the placebo group. The most commonly reported adverse events in the olaparib group were fatigue (20/31; 65%), nausea (17/31; 55%), anaemia (15/31; 48%) and dyspnea (13/31; 42%). In the placebo group the most common adverse events were fatigue (25/38; 66%), coughing (22/38; 58%), dyspnea (15/38; 39%) and nausea (11/38; 29%). There were no treatment-related deaths. Interpretation: PFS was longer in the olaparib arm, but this did not reach statistical significance. When the PFS HR was adjusted for smoking status and histology, a significant difference at the one-sided 0.2 level was observed, suggesting that tumour control may be achieved for chemosensitive NSCLC treated with PARP monotherapy. We speculate that this signal may be driven by a molecular subgroup harbouring HRD.
  • EPIC: an evaluation of the psychological impact of early-phase clinical trials in cancer patients

    Jittla, P.; Graham, Donna; Zhou, Cong; Halliwell, J.; O'Reilly, S.; Aruketty, Sreeja; Azizi, Alexander; Germetaki, Theodora; Lowe, Jessica; Little, Martin; et al. (2022)
    Background: Anxiety and depression in patients with cancer is associated with decreased quality of life and increased morbidity and mortality. However, these are often overlooked and untreated. Early-phase clinical trials (EPCTs) recruit patients with advanced cancers who frequently lack future treatment options, which may lead to increased anxiety and depression. Despite this, EPCTs do not routinely consider psychological screening for patients. Patients and methods: This prospective observational study explored levels of anxiety and depression alongside impact of trial participation in the context of EPCTs. The Hospital Anxiety and Depression Scale and the Brief Illness Perceptions Questionnaire were completed at the point of EPCT consent, the end of screening and at pre-specified time points thereafter. Results: Sixty-four patients (median age 56 years; median Eastern Cooperative Oncology Group performance status 1) were recruited. At consent, 57 patients returned questionnaires; 39% reported clinically relevant levels of anxiety whilst 18% reported clinically relevant levels of depression. Sixty-three percent of patients experiencing psychological distress had never previously reported this. Males were more likely to be depressed (P = 0.037) and females were more likely to be anxious (P = 0.011). Changes in anxiety or depression were observed after trial enrolment on an individual level, but not significant on a population level. Conclusions: Patients on EPCTs are at an increased risk of anxiety and depression but may not seek relevant support. Sites offering EPCTs should consider including psychological screening to encourage a more holistic approach to cancer care and consider the sex of individuals when tailoring psychological support to meet specific needs.
  • Reflection on black and ethnic minority participation in clinical trials

    Iyizoba-Ebozue, Z.; Fatimilehin, Abiola; Mbanu, Peter; Adeleke, S.; Department of Clinical Oncology, Leeds Cancer Centre, Leeds, UK (2022)
    None
  • Patterns and timing of recurrence following CRS and HIPEC in colorectal cancer peritoneal metastasis

    Hassan, Sarah; Malcomson, Lee; Soh, Yen Jia; Wilson, Malcolm S; Clouston, Hamish; O'Dwyer, Sarah T; Kochhar, Rohit; Aziz, Omer; The Christie Peritoneal and Oncology Centre, Manchester, M20 4 BX, United Kingdom. (2022)
    Introduction: Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) is an established treatment of Colorectal Peritoneal Metastases (CRPM). This study aims to determine the timing and patterns of recurrent disease on imaging following complete CRS/HIPEC. Methods: Retrospective analysis of a national peritoneal tumour service database identified CRPM patients with complete CRS/HIPEC(CC0) from 2005 to-2018. Patients with<2 years follow-up or and those where post-operative histology from the CRS/HIPEC procedure did not confirm CRPM from their original colorectal cancer were excluded. Time to recurrence was measured from surgery to first radiologically illustrated recurrence. CT was the primary modality used, supplemented by PET-CT or MRI if required. Outcomes of interest were survival data (including overall survival (OS), disease-free survival (DFS) and peritoneal-recurrence free survival (PRFS)), timing and patterns of recurrent disease. Results: 146 of the 176 patients identified were eligible for inclusion. Median OS for all study patients was 45.2 months (95% CI 38-53 months), median DFS was 11.7 months (95% CI 9-14 months), and median PRFS was 25.2 months (95% CI 14.7-30 months). Recurrent disease was seen in 112 cases (77%), radiologically classified as intraperitoneal in 50 patients (44%), single site systemic in 21 patients (19%) and multi-site in 41 patients (37%). CT detection rate for disease recurrence was 88%. Subgroup analyses showed that PCI ≥12, positive nodal primary disease and synchronous peritoneal disease were associated with worse outcomes. Conclusion: Patients selected for CRS/HIPEC for CRPM have an OS > 45 months, with the majority recurring systemically within a year. Peritoneal recurrence is a later event after several years. Surveillance programs in this group should be most intensive in the first 2 years after surgery, using CT with oral and intravenous contrast.
  • A phase I trial of CT900, a novel α-folate receptor-mediated thymidylate synthase inhibitor, with expansion cohorts in patients with high grade serous ovarian cancer

    Banerjee, S.; Michalarea, V.; Ang, J. E.; Ingles Garces, A.; Biondo, A.; Funingana, I. G.; Little, Martin; Ruddle, R.; Raynaud, F.; Riisnaes, R.; et al. (2022)
    Purpose CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR-overexpressing tumours. Patients and methods: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1-6 mg/m2 weekly and 2-12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer (HGSOC) were enrolled in the expansion cohorts. Results: 109 patients were enrolled, 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n=40), the most common treatment related adverse events were fatigue, nausea, diarrhoea, cough, anaemia and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 greater than 600 nM needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21·9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumour evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7·7%) in patients with negative/very low or low expression of α‑FR. Conclusions: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α‑FR expression and warrants further investigation.
  • Spatial gene expression changes in the mouse heart following base-targeted irradiation

    Walls, G. M.; Ghita, M.; Queen, R.; Edgar, K. S.; Gill, E. K.; Kuburas, R.; Grieve, J.; Watson, C. J.; McWilliam, Alan; van Herk, Marcel; et al. (2022)
    Purpose: Radiation cardiotoxicity (RC) is a clinically significant side effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterise late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity. Materials and methods: An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. Following echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis in order to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions. Results: Ejection fraction was reduced at 30 weeks following a 16 Gy irradiation to the heart base, compared with the sham-irradiated control. There were markedly more significant gene expression changes within the irradiated regions compared with non-irradiated regions. Variation was observed in the transcriptomic impact of radiation on different cardiac base structures. eg. between the right atrium (n=86 dysregulated genes), left atrium (n=96 dysregulated genes), and the vasculature (n=129 dysregulated genes). Disrupted biological processes spanned extracellular matrix, circulatory, neuronal and contractility activities. Conclusions: This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity, and support the development of actionable targets for pharmacological intervention, and biologically relevant dose constraints.
  • Interior design: a new perspective in supportive care of patients with acute onset of debilitating diseases

    Mauri, D.; Kampletsas, E.; Smyris, G.; Tsali, L.; Tsekeris, P.; Harissis, H.; Kamposioras, Konstantinos; Tolia, M.; Hyphantis, T.; Ntellas, P.; et al. (2021)
    Background: Upon the onset of a debilitating rapidly evolving condition (such as cancer or a rapidly progressing myopathy, neuropathy, respiratory disease, or a severe traumatic injury), individuals have limited time to find a new home or make radical structural modifications in their residence. How the affected patients can continue sharing the same house with their families, while meeting their own special requirements, is thus rising as a critical issue. Household and daily routine rearrangements, either temporary or permanent, may be necessary, to ameliorate the life of patients with impairments, lasting for months or even years. Objectives: Interior design may provide a highly efficient "living" palliation for debilitating medical conditions directly at patients' home-site. Methods: Research of relevant literature, using keywords "debilitating conditions," "home care," "end of life care," "care of advanced cancer patients," "care of patients with mental disorders," "home care of covid-19 affected patients," and "care of patients with degenerative illnesses." Results: We found that patients and their relatives may not be aware of the probable interior design solutions to their daily life challenges, imposed by a disease-related impairment. In parallel, interior design experts may equally be unaware of these issues, as well as of who needs the available solutions.Similarly, medical and architectural sciences are not connected, eventually failing to meet patients' everyday needs. Conclusions: Interior architecture and health scientists are called to cooperate, aiming to provide a highly efficient and meaningful support to patients and families affected by unforeseen debilitating medical conditions.
  • Activity of cabazitaxel in metastatic or inoperable locally advanced dedifferentiated liposarcoma: A phase 2 study of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG)

    Sanfilippo, R.; Hayward, R. L.; Musoro, J.; Benson, C.; Leahy, Michael G; Brunello, A.; Blay, J. Y.; Steeghs, N.; Desar, I. M. E.; Ali, N.; et al. (2022)
    Importance: Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. New drugs are required. Objective: To assess whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DDLPS to justify further investigation in a phase 3 setting. Design, setting, and participants: This international multicenter, open-label single-arm phase 2 trial was conducted at 10 institutions in 4 European countries from March 2015 to March 2019. Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months and had to have received no more than 1 previous line of chemotherapy. Interventions: After mandatory central review of tumor blocks, if the DDLPS diagnosis was confirmed, patients started treatment within 72 hours after registration. Cabazitaxel was administered at a dose of 25 mg/m2 IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent. Main outcomes and measures: The primary end point was progression-free survival (PFS) rate at 12 weeks per RECIST 1.1. Based on a Simon 2-stage design, at least 4 of 17 (stage 1) and 11 of 37 (stage 2) eligible and evaluable patients who were progression free at 12 weeks were needed. The final analysis report was completed on November 17, 2021. Results: Forty patients were registered, with 2 patients being ineligible. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Progression-free survival at 12 weeks was 55%, achieving the primary study end point. At a median follow-up of 21.6 months, median PFS was 6 months and median OS 21 months. Response rate (RR) was 8% with 1 clinical response (CR) and 2 partial responses (PR). Twenty-three (60.5%) patients had a stable disease (SD). Disease control (PR+SD) was achieved in 26 patients (68%). Conclusions and relevance: This nonrandomized phase 2 clinical trial met its primary end point, with 21 of 38 patients (55%) being progression free at 12 weeks. These results suggest important activity of cabazitaxel in patients with metastatic or inoperable locally advanced DDLPS. The drug is worth being further studied in these tumors in a phase 3 setting.

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