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Background In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES. Methods Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2‐6 [D2‐6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re‐escalation in cohort C. In arm 2, patients were assigned to NIR (days 1‐7 [D1‐7]) and escalating doses of IRN (D2‐6). Results From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose‐limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1‐7 plus TMZ at 30 mg/m2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m2 every day on D2‐6 (arm 2). One confirmed partial response was observed in arm 2; the median progression‐free survival was 9.0 weeks (95% CI, 7.0‐10.1 weeks) and 16.3 weeks (95% CI, 5.1‐69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP‐ribose) activity was 89% (range, 83%‐98%). Conclusions The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple‐combination study of NIR, IRN, and TMZ has commenced., Preclinical evaluations have identified the EWS‐FLI1 translocation, pathognomonic of Ewing sarcoma, as a predictive factor of response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors with synergistic cell death in vivo with DNA damaging agents. This phase 1 study examines the dosing and safety of a combination of the PARP inhibitor niraparib with temozolomide or irinotecan.

The largest whole genome sequencing (WGS) endeavour involving cancer and rare diseases was initiated in the UK in 2015 and ran for 5 years. Despite its rarity, sarcoma ranked third overall among the number of patients' samples sent for sequencing. Herein, we recount the lessons learned by a specialist sarcoma centre that recruited close to 1000 patients to the project, so that we and others may learn from our experience. WGS data was generated from 597 patients, but samples from the remaining approximately 400 patients were not sequenced. This was largely accounted for by unsuitability due to extensive necrosis, secondary to neoadjuvant radiotherapy or chemotherapy, or being placed in formalin. The number of informative genomes produced was reduced further by a PCR amplification step. We showed that this loss of genomic data could be mitigated by sequencing whole genomes from needle core biopsies. Storage of resection specimens at 4 °C for up to 96 h overcame the challenge of freezing tissue out of hours including weekends. Removing access to formalin increased compliance to these storage arrangements. With over 70 different sarcoma subtypes described, WGS was a useful tool for refining diagnoses and identifying novel alterations. Genomes from 350 of the cohort of 597 patients were analysed in this study. Overall, diagnoses were modified for 3% of patients following review of the WGS findings. Continued refinement of the variant‐calling bioinformatic pipelines is required as not all alterations were identified when validated against histology and standard of care diagnostic tests. Further research is necessary to evaluate the impact of germline mutations in patients with sarcoma, and sarcomas with evidence of hypermutation. Despite 50% of the WGS exhibiting domain 1 alterations, the number of patients with sarcoma who were eligible for clinical trials remains small, highlighting the need to revaluate clinical trial design.

Background A randomised phase II trial demonstrated that the addition of olaratumab to doxorubicin significantly increased overall survival (OS) in patients with advanced soft tissue sarcomas (STS) compared to doxorubicin alone. The recently presented phase III study of doxorubicin and olaratumab in advanced soft tissue sarcoma was discordant with this finding. Methods We performed a retrospective analysis of adult patients with advanced-/metastatic STS treated with at least two cycles of doxorubicin and olaratumab at eight sarcoma units across England and Northern Ireland between May 2017 and March 2019. Results 172 patients were evaluable and 40 patients (23.3%) had died at the time of analysis. Median ECOG performance status (PS) was 1. Median progression free survival (PFS) was 6.8 months (95% CI 5.9–7.7 months). Leiomyosarcoma was the most common histological subtype (75 patients, 43.6%), followed by liposarcomas (19, 11.0%). The mean number of cycles was 5 (doxorubicin range 2–6; olaratumab range 2–23). Two patients (1.2%) had a complete response and 34 (19.8%) had a partial response. 79 (45.9%) had stable and 58 (33.7%) progressive disease. 57 patients (33.1%) experienced grade ≥ 3 neutropenia and 7 patients (4.1%) grade ≥ 3 febrile neutropenia. Grade ≥ 3 anaemia was seen in 21 patients (12.2%). Grade ≥ 3 non-haematological toxicities were seen in 35 patients (20.3%). A clinically significant drop in left ventricular ejection fraction was seen in 6 patients (3.5%). 48 patients (27.9%) required a dose reduction. Overall survival (OS) is pending. Conclusions Our results are in keeping with the phase III study findings: response rate, PFS and OS were similar to those reported in the phase III ANNOUNCE trial.

Purpose: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II bas-ket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. Patients/methods: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or sys-temic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed cen-trally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or par-tial response). If >6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. Results: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confi-dence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data. Conclusion: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. Clinical trial number: EORTC 90101, NCT01524926. 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma. Methods This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2-25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play-performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m(2) per day, capped at 24 mg per day, and etoposide (100 mg/m(2) per day) plus ifosfamide (3000 mg/m(2) per day) were administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274. Findings 30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m(2) combination group and two in the 14 mg/m2 combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m(2) per day (with daily dose cap of 24 mg) and etoposide 100 mg/m(2) per day plus ifosfamide 3000 mg/m2 per day administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34-69) in 18 of 35 patients per the binomial estimate. The most common grade 3-4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred. Interpretation Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189). Copyright (C) 2021 Elsevier Ltd. All rights reserved.

[Background] Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome., [Methods] EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment., [Discussion] This study will establish which is the “standard regimen” of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner., [Trial registration] Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 92192408 on 4 November 2013., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n°602856. The NCC in France, CLB, receives additional funding from SFCE and Ligue contre le cancer. The coordinating sponsor (the University of Birmingham, Birmingham, UK) is funded by Cancer Research UK (grant award reference C5952/A14745).

Background We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). Patients and methods The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. Results In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan–Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. Conclusions The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755)., Highlights • The recommended phase II dose of lenvatinib in children with relapsed/refractory solid malignant tumors is 14 mg/m2. • This dose is equivalent to the recommended dose of 24 mg/day for single-agent lenvatinib in adults with DTC. • Single-agent lenvatinib showed activity of interest in children and young adults with osteosarcoma. • Based on this initial report, lenvatinib is currently being investigated in combination with chemotherapy in osteosarcoma.

Summary Background For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. Methods The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m 2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m 2 on days 1 and 8 and intravenous docetaxel 75 mg/m 2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009–014907–29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. Findings Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7–29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5–54·6] vs 46·4% [37·5–54·8]); median progression-free survival (23·3 weeks [95% CI 19·6–30·4] vs 23·7 weeks [18·1–20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99–1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. Interpretation Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. Funding Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.

Ifosfamide is used to treat soft-tissue sarcoma (STS) and bone sarcoma (BS), with improved efficacy at doses above 9 g/m2/cycle. To mitigate treatment-associated toxicity with higher doses, continuous infusional ifosfamide is increasingly used. However, clinical outcome data remain limited. Single-centre retrospective analysis of patients treated with four-weekly infusional ifosfamide (14 g/m2/14d) between August 2012 and February 2019 was conducted. Radiological response, progression-free survival (PFS), overall survival (OS) and toxicity were evaluated. Eighty patients were treated&mdash, 46 with STS and 34 with BS. Patients received a median of three cycles of infusional ifosfamide (1&ndash, 24). Overall disease control rate (DCR) in STS was 50% (23 of 46 patients), with a median PFS of 3.8 months, and median OS of 13.0 months. In synovial sarcoma (SS), DCR was 80% (12/15), median PFS 8.1 months and median OS 20.9 months. Overall DCR in BS (34 patients) was 30%, with a median PFS of 2.5 months and median OS of 6.2 months. Five patients (6%) stopped treatment due to toxicity alone within the first two cycles. A further 10 patients stopped treatment due to toxicity during later treatment cycles (12%) and 18 patients (23%) required dose modification. Forty-five patients (56%) experienced grade (G) 3/4 haematological toxicity, with 12 episodes of febrile neutropenia and one treatment-related death. Twenty-seven patients (34%) experienced G3/4 non-haematological toxicity, most commonly nausea and vomiting (10, 13%). In summary, infusional ifosfamide has efficacy in STS, most notable in SS. Benefit appears limited in BS. Treatment is associated with toxicity that requires specialist supportive care.

11500 Background: In 2010, different chemotherapy regimens were standard in Europe and the USA for newly diagnosed ES. In the absence of novel agents to investigate, comparison of these two strategies was considered worthwhile. Methods: Newly diagnosed localised or metastatic ES patients aged 5-50 were eligible. Patients were randomized to receive either the European regimen (Arm A) of VIDE (vincristine [V], ifosfamide [I], doxorubicin [D] and etoposide [E]) induction and VAI or VAC (V, actinomycin D and I or cyclophosphamide [C]) consolidation or the USA regimen (Arm B) of compressed VDC/IE induction and IE/VC consolidation. The primary outcome measure was event-free survival (EFS); secondary outcomes included overall survival (OS) and toxicity. The design was Bayesian with interpretation based on posterior probabilities (with non-informative priors) – i.e. probability that true hazard ratio (HR) < 1.0 given the data [Pr(HR200 ml); country (37% UK, 31% France, 32% other). Median follow-up was 1.7 years. The HRs (95% CrI) were 0.70 (0.51, 0.95) for EFS and 0.64 (0.42, 0.96) for OS in favour of Arm B, with posterior probabilities of 98% for both that Arm B was better. Subgroup analyses showed no evidence that this benefit differed depending the baseline features, with no HT being close to significance (table). There were no major differences in acute toxicity: 68% of patients in Arm A experienced serious adverse events and 67% in Arm B. Conclusions: VDC/IE chemotherapy is superior to VIDE for both EFS and OS, with no excess toxicity. This benefit is consistent across all baseline stratification parameters. Clinical trial information: ISRCTN92192408 . [Table: see text]

11524 Background: Survival for RR-ES at 5 years remains < 15%, so novel treatments are needed. Almost all Phase II trials for RR-ES use response as the primary outcome measure. It is unclear whether response is a valid surrogate for survival outcomes. Methods: Patients (pts) were eligible if they had RR-ES and were evaluable for imaging response (primary outcome) if they had measurable disease by RECIST 1.1. The randomization was initially between four chemotherapy regimens: topotecan-cyclophosphamide, irinotecan-temozolomide, gemcitabine-docetaxel (GD), high-dose ifosfamide. Response was assessed after 2, 4 (primary) and 6 cycles of therapy and was classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). PFS and OS were secondary outcomes. Survival from each assessment point by response status was analyzed, by Cox models, with hazard ratios (HR) given for PR v. SD and CR+PR v. SD. Results: From 2015-19, 241 pts with response data were entered. The relationship between response status and PFS and OS is shown in the table (HR < 1.0 indicates better outcome for PR or CR+PR than SD). Both PFS and OS were similar for pts with PR or CR+PR compared to those with SD. OS was inferior for patients with PD (all p < 0.01) (PFS is by definition zero for patients with PD at that timepoint). Small numbers mean CR results are not reliable. Results were consistent across all treatments and between refractory and relapsed disease. At the first interim assessment the GD arm was dropped, with risk ratios for response compared to the other three arms (blinded as still open) of 0.3, 0.5 and 0.5. If a new outcome – disease control (CR+PR+SD) – is defined, the risk ratios are 0.7, 0.8 and 0.7; i.e. still inferior for GD, but less so. Conclusions: Response does not correlate with survival outcomes in RR-ES, so considering PR, or even CR, a success and SD a failure when evaluating treatments may be misleading. We propose PFS as a better primary outcome for future trials and it will be introduced as such in the rEECur trial. Clinical trial information: ISRCTN36453794 . [Table: see text]

Primary bone tumours are rare, accounting for < 0.2% of malignant neoplasms registered in the EUROCARE (European Cancer Registry based study on survival and care of cancer patients) database. Different bone tumour subtypes have distinct patterns of incidence, and each has no more than 0.3 incident cases per 100 000 per year. Osteosarcoma (OS) and Ewing sarcoma (ES) have a relatively high incidence in the second decade of life, whereas chondrosarcoma (CS) is more common in older age.

Summary Background An inflammatory myofibroblastic tumour (IMFT) is a rare mesenchymal neoplasm characterised by anaplastic lymphoma kinase (ALK) gene rearrangements. We assessed the activity and safety of crizotinib, a tyrosine kinase inhibitor, targeting ALK in patients with advanced IMFT either with or without ALK alterations. Methods We did a multicentre, biomarker-driven, single-drug, non-randomised, open-label, two-stage phase 2 trial (European Organisation for Research and Treatment of Cancer 90101 CREATE) at 13 study sites (five university hospitals and eight specialty clinics) in eight European countries (Belgium, France, Germany, Italy, Netherlands, Poland, Slovakia, and the UK). Eligible participants were patients aged at least 15 years with a local diagnosis of advanced or metastatic IMFT deemed incurable with surgery, radiotherapy, or systemic therapy; measurable disease; an Eastern Cooperative Oncology Group performance status of 0–2; and adequate haematological, renal, and liver function. Central reference pathology was done for confirmation of the diagnosis, and ALK positivity or negativity was assessed centrally using immunohistochemistry and fluorescence in-situ hybridisation based on archival tumour tissue and defined as ALK immunopositivity or rearrangements in at least 15% of tumour cells. Eligible ALK -positive and ALK -negative patients received oral crizotinib 250 mg twice per day administered on a continuous daily dosing schedule (the duration of each treatment cycle was 21 days) until documented disease progression, unacceptable toxicity, or patient refusal. If at least two of the first 12 eligible and assessable ALK -positive patients achieved a confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a maximum of 35 patients were to be enrolled. If at least six ALK -positive patients achieved a confirmed response, the trial would be deemed successful. The primary endpoint was the proportion of patients who achieved an objective response (ie, a complete or partial response) as per RECIST 1.1, with response confirmation assessed by the local investigator every other cycle. Activity and safety endpoints were analysed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01524926. Findings Between Oct 3, 2012, and April 12, 2017, we recruited and treated 20 eligible participants, 19 of whom were assessable for the primary endpoint. Median follow-up was 863 days (IQR 358–1304). Six of 12 ALK -positive patients (50%, 95% CI 21·1–78·9) and one of seven ALK -negative patients (14%, 0·0–57·9) achieved an objective response. The most common treatment-related adverse events in the 20 participants were nausea (11 [55%]), fatigue (9 [45%]), blurred vision (nine [45%]), vomiting (seven [35%]), and diarrhoea (seven [35%]). Eight serious adverse events occurred in five patients: pneumonia, fever of unknown cause, a heart attack with increased creatinine and possible sepsis, an abdominal abscess with acute renal insufficiency, and a QT prolongation. Interpretation With 50% of participants with ALK -positive tumours achieving an objective response, crizotinib met the prespecified criteria for success in this trial. The results presented here support the rationale for inhibiting ALK in patients with IMFT. Crizotinib could be considered as the standard of care for patients with locally advanced or metastatic ALK -positive IMFT who do not qualify for curative surgery. Funding The European Organisation for Research and Treatment of Cancer and Pfizer.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. / Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET− sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. / Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET− patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET− cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. / Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. / Clinical trial number: EORTC 90101, NCT01524926

Background Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS. Methods Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK− subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety. Findings Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK− patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3–57.8) with a DOR of 52 d. Further MET+/ALK− efficacy end-points were DCR: 14.3% (95% CI: 0.3–57.8), median PFS: 1.3 months (95% CI: 0.5–1.5) and median OS: 5.6 months (95% CI: 0.7–7.0). The remaining MET+/ALK− and MET−/ALK− patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease. Interpretation Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment. Clinical Trial Number EORTC 90101, ClinicalTrials.gov NCT01524926 .

Background Lenvatinib (LEN) is a multikinase inhibitor of VEGFR1–3 and other targets. We report data from phase Ib dose-finding and phase II expansion cohorts of LEN + etoposide + ifosfamide in pts with r/r osteosarcoma. Methods Pts were aged 2 to ≤ 25 years with r/r osteosarcoma and Results In the phase Ib dose-finding cohort (n = 22), pts received LEN 11 mg/m2 (n = 7) and 14 mg/m2 (n = 15) + chemo. Dose-limiting toxicities were: Grade (G) 4 thrombocytopenia (n = 1; LEN 11 mg/m2), G4 thrombocytopenia and G3 epistaxis (n = 1; LEN 14 mg/m2), G2 oral dysesthesia, G3 muscle spasm, and G2 back pain (n = 1; LEN 14 mg/m2). RPh2D was LEN 14 mg/m2 + chemo. In the expansion cohort (n = 20), the median number of LEN cycles received was 4 (range: 1–7). As reported in the database, the most frequent treatment-emergent adverse events (TEAEs) were platelet count decreased/thrombocytopenia (50%/30%), neutropenia/neutrophil count decreased (45%/25%), anemia (45%), nausea (40%), ALT increased, diarrhea, and white blood cell count decreased (30% each). Most frequent G ≥ 3 TEAEs were neutropenia/neutrophil count decreased (45%/25%), platelet count decreased/thrombocytopenia (40%/20%), white blood cell count decreased (30%), and anemia (25%). Pneumothorax was observed in the dose-finding cohort (n = 6) and expansion cohort (n = 1); 2 (dose-finding cohort) were ≥G3; and 1 was post-thoracotomy. 4 Pts (dose-finding cohort) discontinued treatment due to TEAEs. There were no treatment-related fatal serious AEs. In the dose-finding combination cohort, 12/18 evaluable pts (66.7%) achieved PFS-4. In the phase II expansion cohort, 5/8 evaluable pts (62.5%) achieved PFS-4. Conclusions The combination of RPh2D LEN (14 mg/m2) + chemo had a manageable safety profile with promising preliminary evidence of efficacy. Clinical trial identification NCT02432274. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. Disclosure A. Longhi: Non-remunerated activity/ies, non-financial support: PharmaMar, Takeda; Research grant / Funding (institution): Takeda. M. Casanova: Advisory / Consultancy, advisory role: Bayer; Advisory / Consultancy, advisory role: Lilly; Advisory / Consultancy, advisory role: Roche; Advisory / Consultancy, advisory role: Tesaro. S.S. Bielack: Travel / Accommodation / Expenses, site fees for study preparation: Eisai; Travel / Accommodation / Expenses, personal fees from Clinigen: Clinigen; Travel / Accommodation / Expenses, personal fees from Lilly: Lilly; Travel / Accommodation / Expenses, personal fees from Novartis: Novartis; Travel / Accommodation / Expenses, personal fees from Bayer: Bayer; Travel / Accommodation / Expenses, personal fees from Pfizer: Pfizer; Travel / Accommodation / Expenses, personal fees from Isofol: Isofol; Travel / Accommodation / Expenses, personal fees from Sensorion: Sensorion; Travel / Accommodation / Expenses, personal fees from Ipsen: Ipsen; Advisory / Consultancy, Institution negotiating consultancy agreement with Eisai: Eisai. S. Gallego Melcon: Travel / Accommodation / Expenses: Loxo Oncology; Advisory / Consultancy: Bayer, Eusa. All other authors have declared no conflicts of interest.

11007 Background: 5-year survival of RR-ES is about 15%. Several chemotherapy regimens are used, but without robust evidence. rEECur, the first randomised controlled trial in this setting, is defining a standard of care, balancing efficacy and toxicity. Methods: Patients aged 4 to 50 with RR-ES and fit to receive chemotherapy were randomised 2, 3 or 4 ways between topotecan & cyclophosphamide (TC), irinotecan & temolozomide (IT), gemcitabine & docetaxel (GD) or high-dose ifosfamide (IFOS). Primary outcome measure was objective response (OR) after 4 cycles by RECIST 1.1. Secondary outcomes included PFS, OS and toxicity. A probability-based Bayesian approach was used. The first interim assessment to determine which arm should be closed occurred when 50 evaluable patients had been recruited to 3 arms and evaluated for the primary outcome measure. Results: 242 patients (89% RECIST-evaluable) recruited between 18/12/14 and 21/06/18 were randomised to TC (n=75), IT (71), GD (66) and IFOS (30). Median age was 21 years (range 4 to 49). Patients had: refractory ES (20%), 1st recurrence (63%), >1st recurrence (17%); initial primary disease arose in bone in 60%; disease progression sites were primary site (17%), pleuropulmonary (29%) or other metastatic (54%). Median follow up was 11.3 months. Outcomes in the GD arm were: response rate 11.5% (95% CI: 4.4 to 23%), median PFS 3.0 months (95% CI: 1.6 to 8.0), median OS 13.7 months (95% CI: 10.1 to 23.9). The table shows, for each pairwise comparison of GD with the other arms (randomly labelled A, B, C to maintain blinding of open arms), the probabilities given the observed data that OR, PFS and OS were better for GD than for each other arm (RR: relative risk, HR: hazard ratio). For OR and PFS, all comparisons favoured the other arms. There were fewer grade 3/4 adverse events with GD than with the other arms pooled (58% v. 74%). Conclusions: rEECur has shown that GD is a less effective treatment than TC, IT or IFOS in reducing tumour burden or prolonging PFS in RR-ES. Recruitment continues to the remaining arms. Clinical trial information: ISRCTN36453794. [Table: see text]

Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA.Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization.Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)].The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients.EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Primary malignant bone sarcomas (MBS) are rare and there are few studies examining their incidence and outcome. Here, the incidence and survival of all subtypes of MBS registered in England between 1979 and 2007 were analysed from patient registry data held by the National Cancer Intelligence Network (NCIN). Over 11,002 new cases of MBS were registered, an average of 379 per year. There was no change in incidence demonstrated over the study period (p = 0.08). Although a peak incidence is observed in adolescence, approximately half of MBS are diagnosed in patients over 50 years. An improvement in outcome of MBS was observed between those patients registered from 1979 to 1983 and 1983 to 1987 (p0.0001), but there has been no improvement since. In the most recent period studied (patients diagnosed 1998-2002) 5-year survival was 55% in Ewing sarcoma, 70% in chondrosarcoma, 56% in chordoma and 43% in osteosarcoma. Patients diagnosed with osteosarcoma over the age of 40 years or with a non-extremity tumour have a significantly inferior outcome; 22% 5-year survival40 years compared with 53%40 years (p0.0001) and 16% non-extremity tumour compared to 48% extremity tumour (p0.0001). This population-based study has allowed us to confidently define the English incidence and survival rates of both the commoner bone tumours such as osteosarcoma, and rarer entities such as chordoma as well as groups with inferior outcome. The lack of significant improvement over recent decades for these diseases is cause for concern and further research.

The combination of bortezomib and rituximab was evaluated in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL) and Waldenstrom macroglobulinaemia (WM), in a Phase I and later, a randomized Phase II study. In the randomized study, 42 patients with recurrent/refractory disease received either: bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11 of a 3-week cycle with rituximab 375 mg/m2 on day 1 (21 patients) or: bortezomib 1·6 mg/m2 and rituximab on days 1, 8, 15 and 22 of a 5-week cycle (with rituximab being given only in cycles 1 and 4).Twenty-eight patients were withdrawn (toxicity 16, progression 7, and ‘patient choice’ 5). The main toxicities were neurological, gastro-intestinal and haematological. The overall response rate was 28/42(67%) and by histology: MCL 11/19, FL 8/15, and WM 9/10. Ten of 28 responding patients remained progression-free at 1–3·5 years. Toxicity and efficacy were equivalent between the two groups. The combination has significant toxicity but is effective, particularly in patients with WM.

Background: The multi-tumor phase 2 trial EORTC 90101 (NCT01524926) assessed the activity and safety of the ALK/MET/ROS1 inhibitor C in IMFT, an orphan malignancy associated with ALK rearrangement or copy number changes. Methods: Pts with local diagnosis of advanced/metastatic IMFT consented for shipment of a tumor tissue block and were screened for treatment after central confirmation of the diagnosis by reference pathology. Eligible ALK positive (+) and negative (-) pts received oral C 250 mg bid until RECIST 1.1 progression (PD). ALK+ was defined as at least 15% of tumor cells with rearrangement on FISH (Vysis LSI ALK Dual Color Break Apart Probe, Abbott Molecular) and/or immunohistochemical positivity (ALK MAb Clone CD246, DAKO). A Simon's optimal 2 stage design was implemented. If at least 2 out of the first 12 eligible and evaluable ALK+ pts achieved a confirmed RECIST 1.1 partial or complete response (PR, CR), a maximum of 35 pts were enrolled. If at least 6 had a confirmed PR/CR, the trial would be deemed successful. Results: Between 10/2012 and 04/2017, 13 sites in 8 European countries recruited 35 pts with a local diagnosis of IMFT, of whom only 20 had centrally confirmed IMFT and were treated with C. Among 12 eligible and evaluable ALK+ pts, 6 achieved a confirmed PR or CR, 1 a non-confirmed PR and 5 had stable disease (SD) as best response (ORR 50.0%, 95% confidence interval: 21.1-78.9%). Further efficacy endpoints in ALK+ pts: disease control rate (DCR = CR/PR/SD as best response) 100.0% (73.5-100.0%), 1-year (y) progression free rate (PFR) 73.3 % (37.9-90.6%), 1-y OS rate (OSR) 81.8% (44.7-95.1%). Among 7 eligible and evaluable ALK- pts, 1 achieved a PR, 5 had SD and 1 PD (ORR 14.3%, 0.0-57.9%). Further data in ALK- cases: DCR 85.7% (59.8-100.0%), 1-y PFR 53.6 % (13.2-82.5%), 1-y OSR 83.3% (27.3-97.5%). One additional ALK- case was non evaluable (no measurable disease at baseline). Common related adverse events were nausea (11/20 [55%]), fatigue (9/20 [45%]), blurred vision (9/20 [45%]), vomiting (7/20 [35%]), diarrhea (7/20 [35%]). Conclusions: EORTC can perform precision medicine phase II trials in ultra-rare cancers such as IMFT, with mandatory collection of tissue, real time reference pathology and genetic profiling. With an ORR of 50% and a DCR of 100% in ALK+ disease, C met pre-specified response rate criteria in this trial. The drug achieves long-lasting disease control in the vast majority of ALK+ pts. Sporadic responses and disease stabilization in ALK- cases either suggest limitations of the assays and their cut-offs for target positivity, or the presence of other oncogenic drivers/alternative fusions that may be sensitive to C. Based on the findings of this prospective trial, C should be considered as systemic treatment standard of care for this orphan disease. Citation Format: Patrick Schoffski, Jozef Sufliarsky, Hans Gelderblom, Jean-Yves Blay, Sandra J. Strauss, Silvia Stacchiotti, Piotr Rutkowski, Lars H. Lindner, Michael G. Leahy, Antoine Italiano, Nicolas Isambert, Maria Debiec-Rychter, Raf Sciot, Thomas Van Cann, Sandrine Marréaud, Axelle Nzokirantevye, Sandra Collette, Agnieszka Wozniak. Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE" [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT045.

11527Background: LEN is a multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET. In human pediatric OS xenograft models, LEN enhanced the antitumor activity of IFM + ETP. In a phase (Ph)...

Learning Objectives After completing this course, the reader will be able to: Explain the importance of resistance to anoikis in the development of metastases.Describe the mechanisms of anoikis resistance in EFTs and osteosarcoma and their potential use in development of new therapies. CME This article is available for continuing medical education credit at CME.TheOncologist.com Detection of micrometastatic tumor cells in the bone marrow or peripheral blood of patients with Ewing family of tumors (EFTs) and osteosarcoma has been shown to correlate with poor outcome. Although one of the aims of chemotherapy is eradication of micrometastatic disease, these cells vary phenotypically from primary tumor cells and appear to be more resistant to chemotherapy. As a barrier to metastasis, cells normally undergo a form of cell death termed anoikis after they lose contact with the extracellular matrix or neighboring cells. Tumor cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while traveling through the circulation. Investigating mechanisms of resistance to anoikis, therefore, provides a valuable model to investigate regulation of micrometastatic disease. This review focuses on the current understanding of the mechanisms involved in mediating cell survival and resistance to anoikis in EFTs and osteosarcoma and discusses future studies that may help to identify novel therapeutics targeted at micrometastatic disease.

BACKGROUND: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen.METHODS: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mgm(-2)), cisplatin (70 mgm(-2)) and streptozocin (1000 mgm(-2)) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival.RESULTS: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3-4 toxicity was neutropaenia (28% patients) but grade 3-4 infection was rare (7%). The most frequent non-haematological grade 3-4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and a-fetoprotein.CONCLUSION: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response. British Journal of Cancer (2010) 102, 1106-1112. doi:10.1038/sj.bjc.6605618 www.bjcancer.com Published online 16 March 2010 (C) 2010 Cancer Research UK

10542 Background: This phase II trial assesses the safety and activity of the ALK/MET inhibitor C in 6 different ALK- or MET-driven tumor types including CCSA, an orphan, treatment-refractory malig...

Purpose To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures. Patients and Methods Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-α) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture. Results Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-α of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07). Conclusion Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-α and in vitro sensitivity in a small number of patients.

Temozolomide is an oral alkylating agent that readily crosses the blood-brain barrier and has activity in patients with advanced melanoma. Carboplatin is a convenient outpatient treatment that also has activity in patients with melanoma. The purpose of this study was to assess the safety of a combination of temozolomide and carboplatin, and provide preliminary evidence of efficacy. In all, 30 patients were treated in two stages. In stage 1, patients received temozolomide 750 mg x m(-2), with escalating doses of carboplatin AUC 3-6. In stage 2, patients received temozolomide 1000 mg x m(-2), with increasing doses of carboplatin until dose-limiting toxicity (DLT) was experienced. In stage 1, 12 patients received 33 cycles of treatment. No grade 3/4 haematological toxicity was experienced up to carboplatin AUC 6. In stage 2, 18 patients received 55 cycles of treatment. The DLT was haematological with grade 4 myelosuppression seen with carboplatin AUC 5. In all, 11 patients were treated with carboplatin AUC 4 to gain further information on toxicity. Myelosuppression remained significant and common with grade 4 thrombocytopenia experienced in 50% of cycles. Two of 28 patients (7%) assessable for efficacy achieved a partial response. None of the 11 patients with brain metastases responded to treatment. The addition of carboplatin to temozolomide 1000 mg x m(-2) significantly adds to toxicity with frequent grade 3/4 myelosuppression. Preliminary information on efficacy demonstrates that it is unlikely that the combination can be given in doses sufficient to improve on the efficacy of temozolomide alone.

Introduction The treatment of locally advanced or metastatic soft tissue sarcoma remains a significant clinical challenge, with overall survival rates of approximately 12 months observed with current first line palliative chemotherapy. A recently completed randomised phase III clinical trial entitled GeDDiS (ISRCTN07742377), was designed to compare first line treatment with gemcitabine in combination with docetaxel (GemDoc) versus current standard treatment with doxorubicin. A pharmacogenetic sub-study was incorporated into the trial to assess potential impact of single nucleotide polymorphisms (SNPs) in genes associated with the pharmacology of the three drugs. Methods A total of 240 patients were recruited to the sub-study with 119 on the doxorubicin arm and 121 on the GemDoc arm. A 4 ml blood sample was taken from each participant and genomic DNA extracted. Individual candidate SNPs were assessed by Taqman PCR in 7 genes associated with doxorubicin pharmacology, 7 genes associated with gemcitabine and 5 genes associated with the pharmacology of docetaxel. Association between the SNPs and efficacy and toxicity was assessed. Results SNPs within the solute transporter SLC22A16, associated with the intracellular influx of doxorubicin, were associated with worse PFS (HR = 1.72, p=0.04) and decreased frequency of grade 3/4 adverse events (71% vs 48%, p=0.04) in the doxorubicin arm of the study but not in the GemDoc arm. Conclusions The association of genetic variants of SLC22A16 with decreased efficacy and decreased incidence of toxicity is consistent with a loss of function in the transporter and previous observation of increased AUC in pharmacokinetic studies assuming that distribution of the drug into target and collateral tissues is restricted. Citation Format: David Jamieson, Beatrice Seddon, Katja Kuever, Hakim-Moulay Dehbi, Sandra Strauss, Sandy Beare, Gareth Veal. Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5029. doi:10.1158/1538-7445.AM2017-5029

BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and young people. Efficacy of multiagent MAP (methotrexate, doxorubicin [Adriamycin], cisplatin) chemotherapy may be influenced by multiple cellular pathways. This pilot study aimed to investigate the association of 36 candidate genetic polymorphisms in MAP pathway genes with histological response, survival, and grade 3-4 chemotherapy toxicity in osteosarcoma. METHODS: Blood samples were obtained from 60 patients who had completed MAP chemotherapy. All patients were manually genotyped for 5 polymorphisms. The remaining 31 polymorphisms were genotyped in 50 patients using the Illumina 610-Quad microarray. Associations between candidate polymorphisms and histological response, progression-free survival, and toxicity were estimated using Pearson chi-square and Fisher exact tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model. RESULTS: Poor histological response was increased in variants of ABCC2 c.24C>T (P = .011) and GSTP1 c.313A>G p.Ile105Val (P = .009), whereas MTHFD1 c.1958G>A p.Arg653Gln was protective (P = .03). Methotrexate toxicity was increased in variants of MTHFR c.1298A>C p.Glu429Ala (P = .038), ABCB1 c.3435T>C Ile145Ile (P = .027), and ABCC2 c.3563T>A p.Val1188Glu (P = .028). Variants of GSTP1 c.313A>G p.Ile105Val were at increased risk of myelosuppression (P = .024) and cardiac damage (P = .008). CONCLUSIONS: This pilot study represents the most comprehensive study to date examining the role of genetic polymorphisms in osteosarcoma. Although small and retrospective, it shows that several polymorphisms appear to significantly influence toxicity and clinical outcome. These deserve prospective validation in the hope of optimizing treatment for resistant disease and reducing the late effects burden. Cancer 2012. © 2011 American Cancer Society.

Background: Ewing's sarcoma/primitive neuroectodermal tumours (ES/PNET) are aggressive musculoskeletal tumours with a predilection for young people. With current treatments, significant numbers of patients relapse and survival is poor for those with metastatic disease. Objective: To review current experimental treatment strategies in ES/PNET and prospects for the future. Methods: A review of the literature and recent meeting presentations on established and experimental cytotoxic and biological therapies in the treatment of ES/PNET was performed. Results/conclusion: New combinations of conventional and emerging cytotoxics show some promise. Molecular techniques are being used to identify high-risk patients and potential cellular targets. Several novel biologically targeted agents have demonstrated encouraging preliminary clinical efficacy; it is hoped these combined with current chemotherapeutic agents may improve outcome in ES/PNET.

10500 Background: Standard first-line treatment of locally advanced/metastatic soft tissue sarcoma (STS) is Dox. GemDoc has activity in STS and is used in relapsed STS after failure of at least one...

PurposeA multicenter, single-arm study examining efficacy and toxicity of epratuzumab combined with rituximab was conducted in patients with recurrent or refractory non-Hodgkin's lymphoma.Patients and MethodsSixty-five patients were enrolled; 34 patients with follicular lymphoma (FL), 15 patients with diffuse large B-cell lymphoma (DLBCL), and 16 patients with other lymphomas. The patients had received a median of two prior therapies (range, 1 to 4); 23% had received rituximab. Epratuzumab was given at 360 mg/m2intravenously over 60 minutes followed by infusion of 375 mg/m2rituximab, weekly for 4 consecutive weeks.ResultsCombination therapy was well tolerated without greater toxicity than rituximab alone. The objective response (OR) rate was 47% (30 of 64) in assessable patients (46%; 30 of 65 in all patients), being highest in FL (64%; 21 of 33) and DLBCL (47%; seven of 15), and with 24% (eight of 33) and 33% (five of 15) achieving complete response (CR) or complete response unconfirmed (CRu) in these two groups, respectively. Two of six patients with marginal zone lymphoma responded to treatment (one CR). There was a trend for the response rates to be higher in patients with low prognostic index scores (statistically significant with respect to the Follicular Lymphoma International Prognostic Index score in FL patients), with 12 FL patients and three DLBCL patients in groups 0 to 1 having OR (CR/CRu) rates of 83% (33%) and 100% (100%), respectively. The median duration of response was 16 months for FL, with five patients currently progression free for 18 months to 30 months, and 6 months for DLBCL, with two patients currently progression free for 12 months and 18 months.ConclusionEpratuzumab combined with rituximab was well tolerated, demonstrating promising antilymphoma activity that warrants additional study.

Introduction: Rituximab (R) is an integral component of therapy for B-cell lymphoid malignancies; bortezomib (Btz) has shown provocative single agent activity in Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) and Waldenström’s Macroglobulinaemia (WM), providing the rationale for investigating the combination. Patients+Methods: Forty-five adult patients (pts.) (30 men, 15 women) with histologically confirmed recurrent CD20+ve FL, MCL or WM, median age 60 years (range 45-79), FL: 17, MCL: 18, WM: 10, stage III/IV 40 (93%), bone marrow (BM) infiltration 32 (73%), elevated LDH 22 (49%), performance status ≥1 22 (49%), were enrolled in a randomised trial comparing 2 schedules of Brz+R: Arm A (twice weekly) Btz: 1.3mg/m2 (on days 1, 4, 8, 11 of a 21-day cycle) and R: 375mg/m2 (on day 1) for 8 cycles, or Arm B (weekly) Btz: 1.6mg/m2 (on days 1, 8, 15, 22 of a 35-day cycle) and R: 375mg/m2 (on days 1, 8, 15, 22 of cycles 1 and 4) for 6 cycles (23 arm A, 22 arm B). The median number of previous treatments was 2 (range 1-7). Seventeen pts. had received a R-containing regimen, with response lasting >6 months, and 8 high-dose treatment. Response was evaluated using the IWR criteria (Cheson et al, JCO17: 1244, 1999) and the updated response criteria from the 3rd International Workshop on WM (Treon et al, Blood107: 3442, 2006) Results: Ability to deliver the therapy, toxicity and efficacy were equivalent in both arms. The median number of cycles given in arm A was 4 and 5 in arm B. Haematological toxicity (grade≥3: anaemia 0%, neutropenia 25%, thrombocytopenia 22%) was significantly influenced by the high percentage of pts. with BM infiltration and concomitant cytopenia on entry to the trial. The most common non-haematological adverse events were fatigue (76%), nausea (56%), diarrhoea (56%), lethargy (46%). Neurotoxicity occurred in 19 pts. (46%) (10 pts. grade 1, 7 pts. grade 2, 2 pts. grade 3). Btz dose was reduced in 7 pts.; 5 doses were omitted because of neuro or haematological toxicity. In 16 pts., treatment was delayed by 1-14 days and in 24 pts. treatment was stopped prematurely. The reasons for stopping treatment were: treatment-related toxicity 11 pts., progressive disease 9 pts., patient’s preference 3 pts., myocardial infarction 1 pt. One pt. was excluded having been found ineligible post randomisation. Thirty-nine pts. (21 arm A, 18 arm B) are evaluable for response so far, one having only received 1 cycle of therapy, which had to be discontinued because of excessive toxicity. 15/32 were in remission (CR, CRu, PR) at the completion of therapy, 7/7 at “mid-therapy” assessment, and 5 have yet to be evaluated. Thus the overall response rate (RR) presently is 22/39 (56%) (CR, CRu, PR), FL 44%, MCL 46%, WM 90%. Conclusions: The combination was active in pts. with recurrent NHL especially WM (RR 90%), despite multiple previous treatments, The weekly schedule is preferable being more convenient, as efficacious and no more toxic. Further investigation is warranted, despite not insignificant therapy compromising toxicity.

Background: FLIPI has been proposed as an accurate, simple, and validated prognostic index on the basis of routinely performed tests (age > 60 yrs, Ann Arbor stage III-IV, serum LDH level increased, Hg < 12g/dL, and more than four nodal areas involved (Solal-Celigny et al., Blood 2004; 104: 1258–1265). FLIPI has reliably predicted outcome for many follicular lymphoma (FL) patients (pts) treated with chemotherapy and rituximab. Currently, monoclonal antibody (Mab) therapy and a number of radioimmunoconjugates are considered important components of the treatment of FL; therefore, evaluating FLIPI in clinical trials of these modalities is of interest for optimizing therapy. Methods: A subset analysis was performed to assess the impact of FLIPI on the outcome of patients with relapsed/refractory FL enrolled in a larger, multi-center, open label, single-arm study of epratuzumab (humanized anti-CD22 Mab) in combination with rituximab (chimeric anti-CD20 Mab) (Strauss et al., ASCO 2004). Results: A total of 32 pts with FL were treated according to this protocol (4 weekly infusions at full dose of each agent), including 16 pts who had received > 2 prior chemotherapy regimens and 11 pts who had previously received rituximab. Twenty pts (62%) achieved an objective response (OR), including 8 pts (25%) with complete responses (CR, CRu) and 12 (37%) with partial responses, with a median response duration of 16.5 months (95% CI: 6.3 - 25.4) and median time-to-progression (TTP) of 11 months (95% CI: 9.9 - 19.2). Conclusion: Our data indicate that high OR rates and durable CR/CRu’s can be achieved with a combination of rituximab and epratuzumab in pts with low- (0–1) and intermediate-risk (2) FL, who failed multiple prior therapies. OR, CR rates and TTP are similar to rituximab front-line therapy for pts with low tumor burden FL (Solal-Celigny et al., Blood 104: 169a, 2004). The combination of rituximab and epratuzumab was significantly less efficacious for pts with high-risk (3–5) FLIPI ( P =.0.0023 for TTP). This small Phase-II study supports the prognostic value of FLIPI for pts with recurrent FL who are treated with MAbs. Prospective use of FLIPI may facilitate the optimal design of randomized trials using rituximab in combination with epratuzumab in pts with FL. | FLIPI score (No. of pts) | OR (%) | CR/CRu (%) | Median Duration in months (95% CI) | Median TTP in months (95% CI) | TTP P-value* | |:----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------:| ------ | ---------- | ---------------------------------- | ----------------------------- | ------------ | | N/A - Not available due to patients with long TTPs that are still censored (i.e. not reached progression of disease). * - Patients with high (3–5) FLIPI scores versus others, based on the log-rank test. | | 0–1 (11) | 9 (82) | 4 (36) | 15.7 (N/A) | 19.2 (10.3 – 21.3) | 0.0023 | | 2 (9) | 6 (67) | 3 (33) | 18.3 (17.2 – 25.4) | 18.8 (10 – 26.7) | | | 3–5 (12) | 5 (42) | 1 (8) | 6.3 (N/A) | 7.7 (7.1 – 10.2) | | Results stratified by FLIPI risk groups

Introduction: The 26S proteasome is an important regulator of proteins involved in cell cycle progression, cell survival, and transcription of anti-apoptotic proteins via activation of NF-κB. Bortezomib, (VELCADE®) is a potent, selective, reversible inhibitor of the 26S proteasome with demonstrated clinical activity in multiple myeloma for which it gained FDA and EMEA approval. On the basis of encouraging phase I data in lymphoma, a phase II clinical study was undertaken to examine the efficacy and toxicity of bortezomib in pts with relapsed, refractory NHL and HD. Methods: 1.3 mg/m2 bortezomib was administered twice weekly for 2 of 3 weeks to pts who had adequate ECOG performance status (PS) >2, and haematological function with an absolute neutrophil count >1.0 x109/l (0.5 x109/l if bone marrow involvement) and platelets >30 x109/l. Pts were assessed for toxicity at each cycle, re-staged after 4 cycles and received up to 8 cycles of treatment. Results: 32pts, 20 male and 12 female with a median age of 58 yrs (35–75) received a total of 119 cycles of treatment. 11 pts had mantle cell lymphoma (MCL), 10 follicular lymphoma (FL), 4 Waldenstrom’s macroglobulinaemia (WM), and 1 lymphoplasmacytic lymphoma. Other diagnoses included HD (n=3), diffuse large B-cell lymphoma (n=1), ATL (n=1), and diffuse follicle centre lymphoma (n=1). Pts were heavily pre-treated with a median of 3.5 previous therapies (range 1–8) and 12 pts (38%) had received prior HDT. Sixteen pts (50%) had bone marrow involvement and 13 (40%) a raised LDH. 13 pts (40%) had a ECOG PS of 1 and 7 pts (22%) a PS of 2. The most common grade III-IV toxicities observed in patients, who received a median of 4 cycles of treatment (range 1–8), were thrombocytopenia in 14 pts (45%); fatigue in 8 pts (26%), anaemia in 5 pts (16%) and peripheral neuropathy in 2 pts (6%). Four of 11 pts with MCL initially responded to treatment, 3PR, 1 CR (ORR of 36%); one pt progressed at the end of 8 cycles having required 2 dose reductions. No patients with FL had an objective response at the outcome assessment after a median of 4 cycles (range 1–8) and within a month of completing therapy; however 4 had stable disease and 2 achieved a ‘late response’ with reduction in tumour volumes of 76.7% and 56.1% when assessed 3 mths later. Two pts with WM achieved a PR on the basis of >50% reduction in paraprotein, but with no change in the bone marrow. No patients with HD or other diagnoses responded to treatment. The sensitivity of tumour biopsy samples to bortezomib was examined in vitro in a CD40 ligand primary culture system in 5 pts on the clinical trial, where sensitivity correlated with clinical response. In a larger group of patients the median EC50 for MCL (n=5) was 209nM, and FL (n=8) 1311nM (p Conclusion: The first European report of bortezomib in pts with relapsed/refractory NHL/HD demonstrates encouraging efficacy in MCL, evidence of activity in WM, and a suggestion of ‘late responses’ in FL. Clinical activity correlated with in vitro sensitivity to bortezomib and continues to be assessed as a potential predictor for response to treatment.

6579 Background: The humanised anti-CD22 monoclonal antibody, epratuzumab has shown clinical single agent anti-lymphoma activity. Here, we report interim results from a multi-centre, open-label, single-arm study of epratuzumab in combination with rituximab in patients with relapsed/refractory B-cell NHL. Methods: Sixty-five pts (57% male; 43% female) with a median age of 61 yrs (range 23–87, 30% >65) were enrolled, 45 with indolent histology (36, follicular lymphoma) and 20 pts with aggressive histology (13, DLBCL). Three pts had stage II, 20 stage III, and 42 stage IV disease; 43% had bone marrow involvement; 37% an elevated LDH; 35% had >2 prior treatments with a median time from last therapy of 1.1 yr (range 0.1–12); and 77% of pts were rituximab-naive. Pts received 360 mg/m2 of epratuzumab i.v. over 60 mins followed by infusion of 375 mg/m2 of rituximab weekly for four consecutive weeks. Results: Combination antibody therapy was well tolerated; 44 pts (68%) experienced 1 or more adverse events (AEs). ...