Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.

Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.

BACKGROUND: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma. METHODS: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3. FINDINGS: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred. INTERPRETATION: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies. FUNDING: Adaptimmune.

Clinical benefit and fragility evaluation of systemic therapy trials for advanced soft tissue sarcoma.

BACKGROUND: The clinical benefit of systemic anticancer therapies can be unclear despite positive trials, and outcomes may not translate to real-world practice. This study evaluated the benefit of soft tissue sarcoma (STS) treatments using the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (MCBS) v1.1 and measured the robustness of STS trial results using Fragility Index (FI). METHODS: Database searches for adult phase II or III trials in advanced STS (January 1998-December 2023) were performed. Therapies with trial outcomes that met the criteria for MCBS were scored 1-5 (≥4 represents substantial clinical benefit). For randomized clinical trials with positive time-to-event endpoints, the number of additional events that would render results nonsignificant, FI, was calculated and expressed as a proportion of the experimental arm size (fragility quotient [FQ]). Higher FI/FQ implies more robust results. RESULTS: Among 194 trials, 19 (9.8%) were phase III. Most phase II trials (146/175; 83.4%) had single-arm or non-comparative design. Trials that were eligible for MCBS scoring (n = 78; 40.2%) evaluated 56 different agents/regimens. Median MCBS score was 2. Only three agents/regimens (all cytotoxic therapies) had an MCBS score ≥4. Among 47 randomized clinical trials, 16 (8 phase II; 8 phase III) trials had positive outcomes. Median FI was 7 (range, 2-52) and 10 trials (62.5%) had an FQ < 10%, with median of 7% (range, 1%-59%). CONCLUSIONS: Most systemic therapies in STS trials did not confer substantial clinical benefit per European Society of Medical Oncology-MCBS. Additionally, positive randomized trials were often fragile. Novel STS therapy trials should use clinically meaningful endpoints and real-world efficacy confirmation is essential, especially for less robust trials.

A tailored phase I-specific patient-reported outcome (PRO) survey to capture the patient experience of symptomatic adverse events.

BACKGROUND: Patient perspectives are fundamental to defining tolerability of investigational anti-neoplastic therapies in clinical trials. Phase I trials present a unique challenge in designing tools for efficiently collecting patient-reported outcomes (PROs) given the difficulty of anticipating adverse events of relevance. However, phase I trials also offer an opportunity for investigators to optimize drug dosing based on tolerability for future larger-scale trials and in eventual clinical practice. Existing tools for comprehensively capturing PROs are generally cumbersome and are not routinely used in phase I trials. METHODS: Here, we describe the creation of a tailored survey based on the National Cancer Institute's PRO-CTCAE for collecting patients' perspectives on symptomatic adverse events in phase I trials in oncology. RESULTS: We describe our stepwise approach to condensing the original 78-symptom library into a modified 30 term core list of symptoms which can be efficiently applied. We further show that our tailored survey aligns with phase I trialists' perspectives on symptoms of relevance. CONCLUSIONS: This tailored survey represents the first PRO tool developed specifically for assessing tolerability in the phase I oncology population. We provide recommendations for future work aimed at integrating this survey into clinical practice.

A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer.

BACKGROUND: This Phase 1b study (B2151002) evaluated the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with other anti-tumour agents in advanced solid tumours. METHODS: Patients with various malignancies were administered gedatolisib (90‒310 mg intravenously every week [QW]) plus docetaxel (arm A) or cisplatin (arm B) (each 75 mg/m2 intravenously Q3W) or dacomitinib (30 or 45 mg/day orally). The safety and tolerability of combination therapies were assessed during dose escalation; objective response (OR) and safety were assessed during dose expansion. RESULTS: Of 110 patients enrolled, 107 received gedatolisib combination treatment. Seven of 70 (10.0%) evaluable patients had dose-limiting toxicities; the most common was grade 3 oral mucositis (n = 3). Based upon reprioritisation of the sponsor's portfolio, dose expansion focused on arm B, gedatolisib (180 mg QW) plus cisplatin in patients (N = 22) with triple-negative breast cancer (TNBC). OR (95% CI) was achieved in four of ten patients in first-line (overall response rate 40.0% [12.2-73.8%]) and four of 12 in second/third-line (33.3% [9.9-65.1%]) settings. One patient in each TNBC arm (10%, first-line; 8.3%, second/third-line) achieved a complete response. CONCLUSIONS: Gedatolisib combination therapy showed an acceptable tolerability profile, with clinical activity at the recommended Phase 2 dose in patients with TNBC. CLINICAL TRIAL: ClinicalTrial.gov: NCT01920061.

Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors.

BACKGROUND: GSK3368715, a first-in-class, reversible inhibitor of type I protein methyltransferases (PRMTs) demonstrated anticancer activity in preclinical studies. This Phase 1 study (NCT03666988) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced-stage solid tumors. METHODS: In part 1, escalating doses of oral once-daily GSK3368715 (50, 100, and 200 mg) were evaluated. Enrollment was paused at 200 mg following a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants, resuming under a protocol amendment starting at 100 mg. Part 2 (to evaluate preliminary efficacy) was not initiated. RESULTS: Dose-limiting toxicities were reported in 3/12 (25%) patients at 200 mg. Nine of 31 (29%) patients across dose groups experienced 12 TEEs (8 grade 3 events and 1 grade 5 pulmonary embolism). Best response achieved was stable disease, occurring in 9/31 (29%) patients. Following single and repeat dosing, GSK3368715 maximum plasma concentration was reached within 1 h post dosing. Target engagement was observed in the blood, but was modest and variable in tumor biopsies at 100 mg. CONCLUSION: Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination. TRIAL REGISTRATION NUMBER: NCT03666988.

Desmoid Tumors in Familial Adenomatous Polyposis Patients: Favorable Outcomes with Multidisciplinary Management.

OBJECTIVE: In this study, we aimed to describe the clinical features, management, and outcomes of desmoid tumors (DTs) in familial adenomatous polyposis (FAP) patients at a high-volume sarcoma center. METHODS: Consecutive patients with FAP and DTs were identified from our institutional databases (1985-2021). Patient demographics, treatment, and outcomes were described. Categorical data were compared using Fisher's exact test, and Kaplan-Meier curves were used to estimate progression-free survival (PFS). RESULTS: Forty-five patients with 67 DTs were identified: 39 mesenteric or retroperitoneal (58.2%), 17 abdominal wall (25.4%), 4 extremity (6%), 4 breast (6%) and 3 back (4.4%). Severe DT symptoms were present in 12 patients (26.7%). Initial treatments per tumor were observation in 30 (44.8%) DTs, chemotherapy in 15 (22.4%) DTs, surgery in 10 (14.9%) DTs, and other systemic therapies in 10 (14.9%) DTs. The majority of DTs remained stable with observation or a single intervention (77.8%). Median PFS was 23.4 years (95% confidence interval 7.6-39.2). In the 12 severely symptomatic patients, four patients required more than two interventions for DT control. At a median follow-up of 6.0 years (range 0.7-35.8 years), 33 (73.3%) patients were alive with disease, 7 (15.6%) were alive without disease, and 5 (11.1%) died of other causes. No patients died of DT-related complications. CONCLUSIONS: The majority of DTs in FAP patients remained stable with observation or a single intervention. There were no DT-related deaths; however, 12 of 45 patients (26.7%) experienced significant tumor morbidity and required more interventions for disease control. Further studies on quality of life are required.

Evaluation of the patient experience of symptomatic adverse events on Phase I clinical trials using PRO-CTCAE.

BACKGROUND: Adverse event (AE) reporting in early-phase clinical trials is essential in determining the tolerability of experimental anticancer therapies. The patient-reported outcome version of the CTCAE (PRO-CTCAE) evaluates AE components such as severity and interference in daily life. The aim of this study was to correlate the grade of clinician-reported AEs with patients' reported experience of these toxicities using PRO-CTCAE. METHODS: Patients with advanced solid tumours enrolled on Phase I clinical trials were surveyed using the PRO-CTCAE. Symptomatic AEs were recorded by physicians using the CTCAE. A logistic regression model was used to assess associations between CTCAE grade and PRO responses. RESULTS: Of 219 evaluable patients, 81 experienced a high-grade (3/4) clinician-reported symptom, and of these, only 32 (40%) and 26 (32%) patients concordantly reported these as either severe or very severe, and interfering with daily life either 'quite a bit' or 'very much', respectively. Of the 137 patients who experienced a low-grade (1/2) clinician-reported AE as their worst symptom, 98 (72%) and 118 (86%) patients concordantly reported these as either mild-moderate severity and minimally interfering with daily life, respectively. There was a statistically significant association between clinician-reported AE grade and interference. Interference scores were also associated with dose reductions. CONCLUSION: This is the first study to explore patient-reported severity and interference from symptomatic toxicities and compare clinician grading of the same toxicities. The study provided further evidence to support the added value of the PRO-CTCAE in Phase I oncology trials, which would make AE reporting patient-centred. Further work is needed to determine how this would affect the assessment of tolerability.

Canadian consensus on TRK-inhibitor therapy for NTRK fusion-positive sarcoma.

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

BACKGROUND: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. METHODS: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. RESULTS: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. CONCLUSIONS: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

Selinexor, a First in Class, Nuclear Export Inhibitor for the Treatment of Advanced Malignant Peripheral Nerve Sheath Tumor.

Malignant peripheral nerve sheath tumor (MPNST) is a highly malignant neoplasm arising from peripheral nerve or its attendant sheath and is derived from Schwann or pluripotent cells of neural crest origin. Patients with recurrent, unresectable, or advanced stage disease have limited treatment options, and current therapies are associated with little benefit. In this article, we report nine cases of MPNST treated with selinexor, an orally bioavailable, selective inhibitor of nuclear export, accompanied by tumor stabilization or regression.

Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma.

Objective: Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma. Materials & methods: HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size). Results: Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time. Conclusion: Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo.

Lay abstract The goal of this study was to compare the health-related quality of life (HRQoL) of patients with advanced unresectable dedifferentiated liposarcoma treated with selinexor compared with those treated with placebo. HRQoL was measured prior to treatment initiation and at the first day of each cycle of their treatment using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Pain scores worsened for placebo compared with selinexor across all visits after treatment, but differences at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms worsened over time reflecting the progressive disease burden in this patient population. As pain is one of the most devastating symptoms associated with advanced and progressing cancers, the significant reduction in pain in the selinexor arm, according to patient perception, represent a relevant added value of this drug in dedifferentiated liposarcoma.

Curability of patients with lymph node metastases from extremity soft-tissue sarcoma.

BACKGROUND: Lymph node metastases (LNM) rarely occur in adult extremity soft-tissue sarcoma (STS), affecting approximately 5% of patients. To the authors' knowledge, few studies to date have evaluated the prognosis and survival of patients with LNM. METHODS: A retrospective review was performed of a single-center, prospectively collected STS database. Demographic, treatment, and oncologic data for patients with STS of the extremity with LNM were obtained from clinical and radiographic records. RESULTS: Of 2689 patients with extremity STS, a total of 120 patients (4.5%) were diagnosed with LNM. LNM occurred most frequently among patients diagnosed with clear cell sarcoma (27.6%), epithelioid sarcoma (21.9%), rhabdomyosarcoma (17.3%), angiosarcoma (14.0%), and extraskeletal myxoid chondrosarcoma (9.3%). A total of 98 patients (81.7%) underwent LNM surgical resection. Patients with isolated LNM had a greater 5-year overall survival (57.3%) compared with patients with American Joint Committee on Cancer (AJCC) eighth edition stage IV STS with only systemic metastases (14.6%) or both LNM and systemic disease (0%; P < .0001). Patients with isolated LNM had an overall survival rate (52.9%) similar to that of patients with localized AJCC stage III tumors (ie, large, high-grade tumors) (49.3%) (P = .8). Patients with late, isolated, metachronous LNM had a 5-year overall survival rate (61.2%) that was similar to that of patients with isolated synchronous LNM at the time of presentation (53.6%) (P = .4). CONCLUSIONS: Many different types of STS develop LNM. Patients with extremity STS with isolated LNM should not be considered as having stage IV disease as they are according to the current AJCC eighth edition classification because they have significantly better survival than those with systemic metastases. Patients with isolated, late, metachronous LNM have a survival similar to that of patients with isolated synchronous LNM at the time of presentation. LAY SUMMARY: The results of the current study demonstrated that patients diagnosed with isolated lymph node metastases have a prognosis similar to that of patients diagnosed with localized American Joint Committee on Cancer stage III soft-tissue sarcomas, which also equates to a significantly better overall survival compared with patients with systemic metastases. Therefore, the authors recommend modifications to the most recent eighth edition of the American Joint Committee on Cancer staging system to clearly distinguish patients with isolated lymph node metastases to acknowledge their better prognosis compared with those with systemic metastases.

Development of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM): A toxicity subscale to measure quality of life in patients with cancer who are treated with ICMs.

BACKGROUND: Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL. METHODS: Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale. RESULTS: Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items. CONCLUSIONS: To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.

A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors.

Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for intravenous administration. On cleavage by plasma esterases, the active principle (AP = idasanutlin) is released. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day dosing schedule every 28 days. Dose escalation used the Bayesian new continual reassessment model. Accelerated dose titration was permitted until grade ≥2 drug-related AEs were observed. The target DLT rate to define the MTD was 16-25%. p53 activation was assessed by measuring macrophage inhibitory cytokine-1 (MIC-1). Results Forty-one patients received 14-120 mg AP; 39 were DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug to AP and an approximately linear and dose-proportional dose-exposure relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. MIC-1 increases were exposure dependent. Stable disease was observed in 14 patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development.

High prevalence of persistent emotional distress in desmoid tumor.

OBJECTIVE: Clinical experience suggests a high prevalence of emotional distress in patients with desmoid tumor (DT). We examine longitudinal Distress Assessment and Response Tool (DART) scores to estimate prevalence and persistence of distress, and compare cross-sectional data between DT and malignant sarcoma cohorts, to identify predictors of distress. METHODS: Patients with DT completed DART at: T1-diagnosis, T2-during, T3-<6 months, and T4-≥6 months, post-treatment. DART includes patient-reported outcome measures of physical symptoms (ESAS-r), depression (PHQ-9), anxiety (GAD-7), and social difficulties (SDI-21). Descriptive prevalence and persistence of anxiety, depression, and wellbeing are reported, and mixed model regression analyses determine predictors of distress. RESULTS: Between 2012 and 2018, a total of 152 DART screens from 94 patients with DT were completed (T1: n = 44, T2: n = 31, T3: n = 22, T4: n = 55). Patients had a mean age 40 years, 78% were female and DT locations were abdominal wall (48%), extremity (30%), and mesentery (22%). Moderate to severe ESAS-r scores (≥4) persisted at T4 for anxiety (20%), depression (13%), and poor wellbeing (31%). Compared to 402 patients with malignant sarcoma, patients with abdominal wall sited DT reported severe PHQ-9 and GAD-7 scores twice as frequently. Abdominal wall location, female sex, history of mood problems, and psychosocial concerns were significant predictors of anxiety, depression, and poor wellbeing in DT. CONCLUSIONS: Adults with DT experience persistently high emotional distress compared to patients with malignant sarcoma. Women with abdominal wall DT, prior mood, and current psychosocial concerns need early attention within multidisciplinary treatment settings to reduce persistent distress.

Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial.

Importance: Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone. Objective: To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS. Design, Setting, and Participants: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater. Interventions: Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy. Main Outcomes and Measures: Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. Results: Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). Conclusions and Relevance: In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02451943.

Hyperprogressive disease in early-phase immunotherapy trials: Clinical predictors and association with immune-related toxicities.

BACKGROUND: A subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) in comparison with pretreatment kinetics; this is known as hyperprogression. This study assessed the relation between hyperprogressive disease (HPD) and treatment-related toxicity and clinical factors. METHODS: This study reviewed patients with solid tumors who were enrolled in early-phase immunotherapy trials at Princess Margaret Cancer Centre between August 2012 and September 2016 and had computed tomography scans in the pre-immunotherapy (reference) and on-immunotherapy (experimental) periods. HPD was defined as progression according to Response Evaluation Criteria in Solid Tumors 1.1 at the first on-treatment scan and a ≥2-fold increase in TGR between the reference and experimental periods. Treatment-related toxicities requiring systemic therapy, drug delays, or discontinuation were considered clinically significant adverse events (CSAEs). RESULTS: Of 352 patients, 182 were eligible for analysis. The median age was 60 years, and 54% were male. The Eastern Cooperative Oncology Group performance status was 0 (32%) or 1 (68%). The Royal Marsden Hospital (RMH) prognostic score was 0/1 in 59%. Single-agent immunotherapy was given to 80% of the patients. Most patients (89%) received anti-programmed death (ligand) 1 antibodies alone or in combination with other therapies. HPD occurred in 12 of 182 patients (7%). A higher proportion of females was seen among HPD patients (P = .01), but no association with age, performance status, tumor type, RMH prognostic score, combination immunotherapy, or CSAEs was found. The 1-year overall survival rate was 28% for HPD patients and 53% for non-HPD patients (hazard ratio, 1.7; 95% confidence interval, 0.9-3.3; P = .11). CONCLUSIONS: HPD was observed in 7% of patients with solid tumors treated with immunotherapy. HPD was not associated with CSAEs, age, tumor type, or the type of immunotherapy but was more common in females.

Feasibility Assessment of Using the Complete Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library.

The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) complements capture of symptomatic adverse events (AEs) by clinicians. Previous trials have typically used a limited subset of relevant symptomatic AEs to reduce patient burden. We aimed to determine the feasibility of administering all 80 AEs included in the PRO-CTCAE library by approaching consecutive patients enrolled in a large academic phase I program at three points in time. Here, we report a preplanned analysis after enrolling the first 20 patients. All items were answered on 51 of 56 potential visits (adherence 91%). Three (5%) additional PRO-CTCAE assessments were partially completed, and two (4%) were missed because of conflicting appointments. No patient withdrew consent or chose not to complete the assessments once enrolled on study. Future trials of experimental drugs that incorporate the PRO-CTCAE should consider using this unselected approach to identify adverse events more completely.

Referrals to a Phase I Clinic and Trial Enrollment in the Molecular Screening Era.

BACKGROUND: Enrichment of patients based on molecular biomarkers is increasingly used in early phase clinical trials. Molecular profiling of patients with advanced cancers can identify specific genomic alterations to inform decisions about investigational treatment(s). Our aim was to evaluate the outcomes of new patient referrals to a large academic solid tumor phase I clinical trial program after the implementation of molecular profiling. MATERIALS AND METHODS: Retrospective chart review of all new referrals to the Princess Margaret Cancer Centre (PM) phase I clinic from May 2012 to December 2014. Molecular profiling using either MALDI-TOF hotspot mutation genotyping or targeted panel DNA sequencing was performed for patients at PM or community hospitals through the institutional IMPACT/COMPACT trials. RESULTS: A total of 971 new patient referrals were included for this analysis. Twenty-seven percent of referrals assessed in clinic were subsequently enrolled in phase I trials. Of all new referrals, 41% had prior molecular profiling, of whom 11% (n = 42) were enrolled in genotype-matched trials. Patients with prior molecular profiling were younger, more heavily pretreated, and had more favorable Princess Margaret Hospital Index (PMHI) scores. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (p = .002), internal referrals within PM (p = .002), and PMHI (p ≤ .001) were independently associated with successful trial enrollment in multivariable analysis. CONCLUSION: Although nearly half of new patients referred to a phase I clinic had prior molecular profiling, the proportion subsequently enrolled into clinical trials was low. Prior molecular profiling was not an independent predictor of clinical trial enrollment. IMPLICATIONS FOR PRACTICE: The landscape of oncology drug development is evolving alongside technological advancements. Recently, large academic medical centers have implemented clinical sequencing protocols to identify patients with actionable genomic alterations to enroll in therapeutic clinical trials. This study evaluates patient referral and enrollment patterns in a large academic phase I clinical trials program following the implementation of a molecular profiling program. Performance status and referral from a physician within the institution were associated with successful trial enrollment, whereas prior molecular profiling was not an independent predictor.