Background This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). Methods Patients with OC (up to two previous platinum-based lines), with a TFIp of 6–12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). Results The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94–1.35; p = 0.197). Grade 3–5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). Conclusions This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6–12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. Clinical trial registration ClinicalTrials.gov, number NCT01379989.

WikiProject Clinical Trials is a Wikidata community project to integrate clinical trials metadata with the Wikipedia ecosystem. Using Wikidata methods for data modeling, import, querying, curating, and profiling, the project brought ClinicalTrials.gov records into Wikidata and enriched them. The motivation for the project was gaining the benefits of hosting in Wikidata, which include distribution to new audiences and staging the content for the Wikimedia editor community to develop it further. Project pages present options for engaging with the content in the Wikidata environment. Example applications include generation of web-based profiles of clinical trials by medical condition, research intervention, research site, principal investigator, and funder. The project's curation workflows including entity disambiguation and language translation could be expanded when there is a need to make subsets of clinical trial information more accessible to a given community. This project's methods could be adapted for other clinical trial registries, or as a model for using Wikidata to enrich other metadata collections.

Objectives Tisotumab vedotin (TV) monotherapy has shown a manageable and tolerable safety profile with clinically meaningful and durable antitumor activity in previously treated r/mCC (Lancet Oncol. 2021;22:609–619). The potential of investigational TV combination regimens in r/mCC was assessed in a multi-cohort phase 1b/2 trial (NCT03786081). Methods Patients with r/mCC with progression on/after or ineligible for/intolerant to standard-of-care were treated with escalating doses of TV + bevacizumab (Arm A) or pembrolizumab (Arm B) or carboplatin (Arm C) all given Q3W (figure 1). Primary objectives were to determine recommended phase 2 dosing (RP2D) and evaluate safety/tolerability. Results A maximum tolerated dose was not reached with any combination. In Arm A, 15 patients received 9 cycles (median) for both TV and bevacizumab. Grade≥3 adverse events (AEs) occurred in 5 patients (33%). The RP2D was TV 2.0 mg/kg + bevacizumab 15 mg/kg Q3W. Five patients had confirmed objective response (cOR). In Arm B, 13 patients received a median of 5 cycles of TV and 4 cycles of pembrolizumab. Grade≥3 AEs occurred in 12 patients (92%). The RP2D was TV 2.0 mg/kg + pembrolizumab 200 mg Q3W. Two patients had cOR. In Arm C, 13 patients received 5 cycles (median) of TV + 4 cycles of carboplatin. Grade≥3 AEs occurred in 8 patients (62%). The RP2D was TV 2.0 mg/kg + carboplatin AUC 5 Q3W. Four patients had cOR. Conclusions TV plus bevacizumab, pembrolizumab, or carboplatin was tolerated and had an acceptable safety profile with encouraging activity in patients with r/mCC.

Objectives Doublet chemotherapy (paclitaxel plus either platinum or topotecan) with bevacizumab (if eligible) is recommended for first–line treatment of recurrent/metastatic cervical cancer (r/mCC; Tewari 2014). In the second–line setting, there are limited data for available treatment options. Tisotumab vedotin (TV) is an investigational antibody–drug conjugate directed to tissue factor. In the phase 2 pivotal trial (innovaTV 204/ENGOT-cx6/GOG-3023) in r/mCC patients with disease progression on or after chemotherapy, TV demonstrated clinically meaningful and durable activity (objective response rate [ORR]: 24%; median duration of response [DOR]: 8.3 months) with a manageable and tolerable safety profile. Most adverse events associated with TV were mild to moderate. These findings support further investigation of TV in patients with r/mCC who progress on first–line treatment. Methods innovaTV 301/ENGOT-cx12/GOG-3057 (NCT04697628) is a global, randomized, open-label, phase 3 trial evaluating efficacy and safety of TV in patients with previously treated r/mCC. Eligible patients are ≥18 years, have r/mCC, and have progressed after 1–2 prior lines of therapy (either standard of care systemic chemotherapy doublet or platinum-based therapy with bevacizumab, if eligible). Approximately 482 patients will be randomized 1:1 to receive 21–day cycles of TV (2.0 mg/kg IV once every 3 weeks) or investigator's choice of chemotherapy: topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed. The primary endpoint is overall survival. Key secondary endpoints are progression-free survival, ORR, time to response, DOR, safety, and quality of life outcomes. The study is enrolling and will have sites in the USA, Europe, Japan, Latin America, Taiwan, Singapore, and South Korea. Results Not applicable. Conclusions Not applicable.

Objectives Low-grade serous ovarian carcinomas (LGSOC) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30–60% of LGSOC. A phase II study of the MEK inhibitor selumetinib showed promising response rate of 15% in LGSOC and binimetinib, a potent MEK1/2 inhibitor, has demonstrated activity across multiple cancers. Methods MILO (MEK-Inhibitor in Low-grade Serous Ovarian Cancer)/ENGOT-ov11 was an open-label, 2:1-randomized study of binimetinib (45-mg BID) vs PCC in LGSOC. Eligible patients had recurrent or persistent measurable LGSOC following ≥1 prior platinum-based chemotherapy, ≤3 prior chemotherapy lines, and no prior MEK-or BRAF-inhibitor. The primary endpoint was progression-free survival (PFS) by blinded central review; additional assessments: overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety.(NCT01849874). Results 303 patients were randomized (201 binimetinib,102 PCC). Median PFS was 9.1 months (95% CI:7.3,11.3) for binimetinib and 10.6 months (95% CI:9.2,14.5) for PCC (HR:1.21(0.79,1.86);closed early for futility). Secondary efficacy endpoints were similar in the two groups: ORR 16%(complete/partial responses[CR/PRs]=32) vs 13%(CR/PRs=13); median DOR 8.1 (range:0.3–12.0+ months) vs 6.7 (0.3–9.7+ months); and median OS 25.3 vs 20.8 months, for binimetinib and PCC, respectively. Safety results were consistent with known safety profile of binimetinib; most common ≥grade 3 events were blood CK increased(20%) and hypertension(20%). Post-hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Conclusions Although MILO did not meet its primary endpoint, binimetinib showed activity in LGSOC across the efficacy endpoints evaluated. Chemotherapy responses were higher than predicted. Further evaluation is warranted.

OBJECTIVES:Pancreatic cancer (PC) and its treatments can result in pancreatic exocrine insufficiency that requires pancreatic enzyme replacement therapy (PERT). Appropriate PERT usage is during meals and snacks. The aim was to determine the frequency of appropriate use of PERT and its impact on symptom alleviation in PC through a patient-reported outcomes online platform. METHODS:Users in the Pancreatic Cancer Action Network's Patient Registry were prompted to answer a standalone questionnaire about their experience with PERT. RESULTS:Two hundred sixty-two users completed the PERT questionnaire (January 2016-January 2018). Patients who reported taking PERT with meals had higher alleviation of symptoms compared with those taking PERT prior to or after meals. Specifically, "feeling of indigestion," "light-colored or orange stools," and "visible food particles in stool" were significantly decreased. Patients taking PERT with meals reported weight gain and less weight loss. CONCLUSIONS:Of the 89% of PC patients prescribed PERT, 65% were prescribed PERT appropriately with all meals and snacks. Overall compliance with PERT administration guidelines was low (50% [105/208]). Improvement in symptoms significantly correlated with appropriate use of PERT. Increase in PC patient and provider education about appropriate PERT usage and administration is warranted.

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This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.

BACKGROUND Scarce systematic trial data have prevented uniform therapeutic guidelines for T‐cell prolymphocytic leukemia (T‐PLL). A central need in this historically refractory tumor is the controlled evaluation of multiagent chemotherapy and its combination with the currently most active single agent, alemtuzumab. METHODS This prospective multicenter phase 2 trial assessed response, survival, and toxicity of a novel regimen in previously treated (n = 9) and treatment‐naive (n = 16) patients with T‐PLL. Induction by fludarabine, mitoxantrone, and cyclophosphamide (FMC), for up to 4 cycles, was followed by alemtuzumab (A) consolidation, up to 12 weeks. RESULTS Of the 25 patients treated with FMC, 21 subsequently received alemtuzumab. Overall response rate to FMC was 68%, comprising 6 complete remissions (all bone‐marrow confirmed) and 11 partial remissions. Alemtuzumab consolidation increased the intent‐to‐treat overall response rate to 92% (12 complete remissions; 11 partial remissions). Median overall survival after FMC‐A was 17.1 months and median progression‐free survival was 11.9 months. Progression‐free survival tended to be shorter for patients with high‐level T‐cell leukemia 1 oncoprotein expression. Hematologic toxicities were the most frequent grade 3/4 side effects under FMC‐A. Exclusively in the 21 alemtuzumab‐consolidated patients, 13 cytomegalovirus reactivations were observed; 9 of these 13 represented a clinically relevant infection. CONCLUSIONS FMC‐A is a safe and efficient protocol in T‐PLL, which compares favorably to published data. Cancer 2013;119:2258–2267. © 2013 American Cancer Society.

Background On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia.Methods Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918.Findings 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0.56 [95% CI 0.46-0.69], p<0.0001); 87% were alive versus 83%, respectively (0.67 [0.48-0.92]; p=0.01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0.0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0.0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group.Interpretation Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia.

5031 Background: Trabectedin (Yondelis, ET-743) is a marine derived compound which binds to the minor groove of DNA distorting the DNA structure and induces apoptosis and cell cycle arrest. It has shown clinical activity in soft tissue sarcoma, ovarian, prostate and breast cancer. Methods: Patients (pts) with recurrent platinum sensitive ovarian carcinoma were randomized in a multicenter, open label study to receive T as 1.5 mg/m2 over 24 h infusion (schedule A) or 1.3 mg/m2 over 3 h infusion (schedule B) both every 3 weeks. All pts received dexamethasone premedication. Primary objective is to evaluate the response rate (RECIST) and secondary objectives are response duration, CA-125 response, time to progression and safety. Results: 107 pts were enrolled in 23 centers. Demographic and disease characteristics were well balanced. Toxicity and response data on the first 99 pts are available: median age 57 (25–78) years; ECOG PS=0: 72% and =1: 28%; pts received a median of 4 cycles (range:1–19 in A, 1–13 in B). Relative dose intensity was 84% and 93% respectively. Objective responses due to investigator’s assessment were 29% (8% CR, 21% PR) with 52% SD in A and 28% (11% CR, 17% PR) with 45% SD in B, with 11 pts not yet evaluable for response. CA 125 responses ≥ 50% occurred in 23% in A and 26% in B. TTP data will be presented. Safety: 501cycles were delivered; the most common any grade drug-related AEs per patient were (A and B) fatigue (56% and 47%), nausea (63% and 70%), vomiting (56% and 45%) and constipation (25% and 30%). Consistent with previous experience, alopecia, stomatitis and neurotoxicity were uncommon and mild/moderate. Grade 3/4 fatigue occurred in 15% in A and 4% in B. Grade 3/4 lab abnormalities were non-cumulative neutropenia (50% and 32%) and reversible ALT increase (58% and 53%). G-CSF support was not routinely given. There were 4 deaths <30 days last infusion date (3 in A unrelated to study drug, one in B due to related multiorgan failure). Conclusions: This analysis suggests that both T schedules appear active with manageable toxicity. There was a trend for less neutropenia and fatigue with schedule B. On the basis of these efficacy results, no additional phase III comparisons between these 2 schedules seem warranted [Table: see text]

Internal tandem duplications (ITDs) of the juxtamembrane region of the FLT3 tyrosine kinase receptor are the most frequent genetic alterations in acute myeloid leukemia (AML). The presence of this mutation has been recognized as an independent poor prognostic factor. In this study, we compared the FLT3 mutational status between diagnosis and subsequent relapses in 31 patients with AML. At diagnosis, seven patients were identified to contain FLT3-ITD mutations and one patient to harbor the D835 mutation. Five patients remained FLT3-ITD positive throughout the disease course (+/+). Three patients lost the FLT3 gene mutation at first (one FLT3-ITD, one D835 mutation), or second relapse (one FLT3-ITD) (+/-). One additional patient lost a small FLT3-ITD positive clone at relapse and at the same time gained an apparently unrelated FLT3-ITD positive clone. One patient without FLT3 mutation at diagnosis relapsed with an FLT3-ITD mutation (-/+). A shorter median duration of first remission (6 months versus 11.5 months) and a higher relapse rate after salvage therapy (e.g. allogeneic peripheral blood stem cell transplantation) resulted in a lower leukemia-free survival in the FLT3 mutated group (11% versus 31%). The loss of a clone with a mutation in the FLT3 gene at relapse did not improve the prognosis.