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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 11549-11549
    Abstract: 11549 Background: Select sarcomas are infiltrated with immunosuppressive myeloid cells. DCC-3014 is an inhibitor of the CSF1R kinase that decreases tumor infiltrating myeloid cells in preclinical models. We hypothesized that DCC-3014 combined with the anti-PDL1 inhibitor avelumab would be safe and tolerable, decrease immunosuppressive myeloid cells, and increase cytotoxic T cells. Methods: This investigator initiated, open label, single center, phase I study of DCC-3014 plus avelumab in patients (pts) with unresectable or metastatic sarcoma utilized a standard 3+3 dose escalation design. DCC-3014 was administered on days 1-3 (loading dose of 20, 30, or 50 mg) followed by oral daily maintenance (10, 14, or 20 mg) in 28-day cycles; 800 mg of IV avelumab was administered q2weeks. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints defined the adverse event (AE) profile and assessed clinical efficacy. Peripheral blood CD14 + Lin - HLA-DR lo myeloid-derived suppressor cells (MDSCs) were measured by flow cytometry. Results: 13 pts were treated; median age was 61 (range 32 – 71), 8 were female, and median prior lines of therapy was 5 (range 2 – 10). Histologic subtypes included leiomyosarcoma (LMS, n = 7), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (LPS, 2), synovial sarcoma (1), and pleomorphic LPS (1). The Table lists treatment-related AEs (TRAEs) of any grade (G) occurring in ≥ 10% of pts and all G ≥ 3 TRAEs, sorted by frequency. All pts had at least 1 TRAE. Seven pts (54%) had a G ≥ 3 TRAE. Most TRAEs were either G ≤ 2 or expected on-target effects of CSF1R inhibition. 1 of 6 pts on the highest dose level had a dose limiting toxicity (G4 elevated AST with abdominal pain) that resolved with treatment cessation. The highest dose level was declared the RP2D. Best objective response by RECIST 1.1 was stable disease in 3 pts; 2 had LMS and were treated at the highest dose level. At baseline, the mean proportion of monocytes in peripheral blood samples with an MDSC phenotype was 12.2% (range 7.1 – 19.9). 5 of 7 pts with serial blood samples had decreased circulating MDSCs (mean decrease of 26.9% from baseline to last time point). Conclusions: DCC-3014 combined with avelumab was safe and tolerable. Study therapy decreased circulating MDSCs in select patients; T cell analyses will be reported. Study expansion at the RP2D is ongoing. Clinical trial information: NCT04242238. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. TPS11590-TPS11590
    Abstract: TPS11590 Background: Dedifferentiated liposarcoma (DDLPS) is characterized by near universal amplification of the cyclin-dependent kinase 4 ( CDK4) gene. Palbociclib (P) is a selective CDK4/6 inhibitor that has demonstrated promise in phase II studies of DDLPS. Anti-PD-1 therapy has also shown signals of efficacy, with an approximate overall response rate of 10% in DDLPS patients. CDK4/6 inhibitors upregulate antigen processing and presentation, suppress regulatory T cells, and increase inflammation within the tumor microenvironment. Combined with anti-PD-1 blockade, they can induce an inflamed T cell phenotype and tumor regression in pre-clinical models. We hypothesize that P combined with the anti-PD-1 inhibitor retifanlimab (R) will be safe and tolerable and have synergistic activity leading to activation of T cells and resultant clinical responses. Methods: NCT04438824 is a phase II study of P plus R with a safety lead-in phase. Patients with unresectable or metastatic DDLPS who have received any number of prior therapies are eligible to enroll. On the safety lead-in phase, 6 patients received P (125 mg once daily orally for 21 days followed by 7 days off) plus R (500 mg IV flat dose), repeated in 28-day cycles. P was initiated as monotherapy two weeks prior to initiation of R. The primary endpoint of the safety lead-in was to confirm the recommended phase two dose of the combination. Accrual to the safety lead-in has been completed and a pre-planned phase II expansion portion was opened to accrual. A study amendment was passed that revised the treatment schedule on the expansion cohort to start both P and R concomitantly on day 1 of each cycle. This revised schedule was based on recent data demonstrating the superior safety of a concurrent, rather than staggered, dosing schedule. The primary endpoint of the expansion phase is to estimate the best overall response rate (ORR) by RECIST 1.1. Secondary endpoints include describing the safety and estimating clinical benefit rate, duration of response, progression-free, and overall survival. A total of 30 patients treated with the revised dosing scheme will be enrolled onto the expansion phase. Twelve patients have been enrolled to date. An ORR of 5% will be considered not promising, while an ORR of 25% will be considered promising. The null hypothesis will be rejected if 4 or more patients have a confirmed objective response to treatment. This design has a type I error rate of 0.06 and a type II error rate of 0.04. Mandatory pre- and on-treatment biopsies will be performed for correlative analyses. Clinical trial information: NCT04438824 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 11570-11570
    Abstract: 11570 Background: The open-label, single-center phase II study of T-VEC and pembrolizumab in patients with advanced sarcoma met its primary endpoint and demonstrated a best objective response rate of 30% at 24 weeks per RECIST v1.1 (Kelly CM, et al, Jama Oncology, 2020). Responses were seen in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, (MFS), epithelioid sarcoma (ES), cutaneous angiosarcoma (AS), and undifferentiated sarcoma not otherwise specified. Here, we report the efficacy observed in three histology specific expansion cohorts: 1) UPS/MFS, 2) cutaneous AS and 3) ES. Methods: Patients refractory to ≥ 1 prior line of systemic therapy or declined standard of care systemic therapy received pembrolizumab intravenously and intratumoral T-VEC injections on day 1 of a 21-day cycle. The primary endpoint was best objective response (ORR, complete and partial responses per RECIST v 1.1) by 24 weeks estimated for each subtype-specific cohort. Secondary objectives included: adverse events (AEs, TRAEs), median PFS and correlatives. Results: Twenty-one patients enrolled in the expansion cohorts: median age 72 years (range: 39-85), male 57%, ≤ 1 prior line of therapy (43%). Treatment was well tolerated in twenty patients; one patient discontinued study therapy due to grade 3 immune mediated hepatitis. Nineteen patients were evaluable for efficacy (one patient withdrew from the study and another discontinued treatment before week 24). Subtype specific best ORR by 24 weeks per RECIST v 1.1: UPS/MFS – 11% (n = 1/9)[95% CI: 0.0-0.48] ; AS – 43% (n = 3/7)[95% CI: 0.1-0.82]; ES – 0% (n = 0/3). The best ORR overall for the AS cohort was 71% (n = 5/7)[95% CI: 0.03-0.95] . Median PFS (weeks) was 14.9 [CI:7-111] for UPS/MFS and 54 [95% CI: 3- not reached] for AS (Table). Conclusions: TVEC and pembrolizumab demonstrated acceptable safety and promising anti-tumor activity in cutaneous AS [head & neck (n = 4) and Stewart-Treves syndrome involving the upper extremity (n = 1)]. Five AS patients experienced a partial response with durable disease control, remaining on study for 1-2 years or more. Two delayed responses were observed in the AS cohort after the pre-specified 24-week criteria. One AS responder progressed on immune checkpoint inhibition prior to study entry. Correlative analyses are ongoing. Clinical trial information: NCT03069378 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: Cancer Research Communications, American Association for Cancer Research (AACR)
    Abstract: The association between immune-related AEs (irAEs) and outcome in patients with sarcoma is not known. We retrospectively reviewed a cohort of patients with advanced sarcoma treated with immune checkpoint blockade (ICB)-based therapy. Association of irAEs with survival was assessed using a Cox regression model that incorporated irAE occurrence as a time-dependent covariate. Tumor samples with available RNA sequencing data were stratified by presence of an irAE to identify patterns of differential gene expression. A total of 131 patients were included. Forty-two (32%) had at least one irAE of any grade and 16 (12%) had at least one Grade ≥ 3 irAE. The most common irAEs were hypothyroidism (8.3%), arthralgias (5.3%), pneumonitis (4.6%), allergic reaction (3.8%), and elevated transaminases (3.8%). Median progression-free survival (PFS) and overall survival (OS) from the time of study entry were 11.4 (95% confidence interval [CI] 10.7 – 15.0) and 74.6 weeks (CI 44.9 – 89.7), respectively. On Cox analysis adjusting for clinical covariates that were significant in the univariate setting, the hazard ratio (HR) for an irAE (HR 0.662, CI 0.421 - 1.041) approached, but did not reach statistical significance for PFS (P = 0.074). Patients had a significantly lower HR for OS (HR 0.443, CI 0.246 – 0.798; P = 0.007) compared to those without or before an irAE. Gene expression profiling on baseline tumor samples found that patients who had an irAE had higher numbers of tumor-infiltrating dendritic cells, CD8+ T cells, and regulatory T cells as well as upregulation of immune and inflammatory pathways.
    Type of Medium: Online Resource
    ISSN: 2767-9764
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 3098144-X
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS11588-TPS11588
    Abstract: TPS11588 Background: New treatment options are needed for sarcomas. Pazopanib is the only targeted agent approved for multiple soft tissue sarcoma (STS) subtypes with a response rate of 6% and a PFS of 4.6 months. Immunotherapy has a limited role in STS, as the SARC028 study of pembrolizumab demonstrated an overall response rate of 18%, with the highest response rate seen in the undifferentiated pleomorphic sarcoma (UPS) cohort at 23%. Lenvatinib is an oral, multi-tyrosine kinase inhibitor approved for the treatment of multiple cancer types including progressive, radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma with inhibitory activity against the receptor tyrosine kinases VEGFR 1-3, FGFR 1-3, KIT, PDGFR alpha/beta, and RET. Early outcomes with the combination of lenvatinib and pembrolizumab suggest that this regimen could be broadly superior to PD-1 targeting alone for several tumor types as high rates of objective response have been noted. The rationale for this study is based on preclinical work demonstrating the immunosuppressive effects of VEGF in the tumor immune microenvironment including inhibition of dendritic cell maturation, recruitment of immunosuppressive Tregs, MDSCs and TAMs and up-regulation of PD-1 on CD8+ cells. Methods: This is a pilot study evaluating the efficacy of lenvatinib and pembrolizumab in the treatment of select metastatic and/or unresectable sarcomas. Patients will be enrolled in one of five cohorts: Cohort A: leiomyosarcoma; Cohort B: UPS; Cohort C: vascular sarcomas (including angiosarcoma and epithelioid hemangioendothelioma); Cohort D: synovial sarcoma and malignant peripheral nerve sheath tumor; and Cohort E: bone sarcomas (limited to osteosarcoma and chondrosarcoma). Eligible patients should have had at least one prior therapy for unresectable and/or metastatic disease, but no more than three prior lines of therapy. Prior treatment with angiogenesis inhibitors or immunotherapy is excluded. Archival tissue is required for eligibility. Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily which will be continued daily thereafter. Subsequently, they will start pembrolizumab 200 mg intravenously every 21 days. The primary endpoint for each cohort is best overall response rate documented by RECIST v1.1 Criteria at 27 weeks. A sample size of 10 patients is planned for each of the five histological cohorts. If 2 or more confirmed responses are observed among the 10 patients in an arm, the drug combination will be considered positive and worthy of further investigation for that arm. Secondary endpoints are PFS, OS, duration of response and safety/tolerability of the combination. On-treatment biopsy and blood samples will be required for correlative assessments. Accrual in all cohorts is ongoing. Clinical trial information: NCT04784247.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 11503-11503
    Abstract: 11503 Background: Prexasertib (PRX) is an inhibitor of CHK1, prevents DNA repair leading to mitotic catastrophe, and can enhance the activity of DNA-damaging chemotherapy. Translocation driven sarcomas exhibit high levels of replication stress and have demonstrated susceptibility to CHK1 inhibition in preclinical models. Desmoplastic small round cell tumor (DSRCT) and rhabdomyosarcoma (RMS) are aggressive sarcomas of children, adolescents and young adults for which novel therapies are urgently required. Methods: We conducted a phase I/II trial of PRX with irinotecan (irino) in patients ≥ 12 months of age with relapsed or refractory DSRCT or RMS. Eligible patients could have any number of prior therapies, including irino. Dose level 1 was PRX 80 mg/m 2 on day 1 + irino 20 mg/m 2 for 10 days. Dose levels 2 and 2A were PRX 105 or 150 mg/m 2 ( 〉 21 years or ≤ 21 years) on day 1 and irino 20 mg/m 2 for 10 (level 2) or 5 (level 2A) days. All cycles were 21 days. The primary objectives were to determine the RP2D of PRX with irino, and to determine the best overall response rate (ORR) in 6 months at the RP2D (RECIST v1.1) in DSRCT, with 3 or more responses out of 16 considered promising. Results: 21 patients were enrolled (DSRCT: 19; 2 RMS:2). The RP2D was dose level 2A. Treatment was well tolerated with the most common adverse events being neutropenia (48%), nausea (48%), and fatigue (52%). Cytopenias were managed with the aid of growth factor support in all patients once the RP2D was established. The DSRCT expansion enrolled 13 of 16 planned patients due to discontinuation of PRX supply prior to study completion. Four patients remain on therapy at the time of this submission. Responses in DSRCT patients at all dose levels are shown in Table. Sixteen of 21 enrolled patients, and 5 of 6 patients achieving PR had previously received irino. The median (range) number of cycles was 7 (2-26). Both RMS patients treated at the RP2D experienced SD as best response. The estimated ORR at the RP2D was 23%, and lower boundary of the one-sided 90% confidence interval was 9%, exceeding the unpromising rate of 5%. The two-sided 90% confidence interval was 7 to 49%. In addition, 3 patients had a PR at doses lower than the RP2D, bringing the ORR for all dose levels (n = 19) to 32% (90%CI: 15 to 53%). Conclusions: The RP2D of PRX in combination with irino is PRX 105 or 150 mg/m 2 ( 〉 21 years or ≤ 21 years) on day 1 and irino 20 mg/m 2 for 5 days in 21 day cycles with myelosuppression successfully managed with growth factor support. The study met its primary objective to consider PRX + irino promising in DSRCT and should be further investigated. Clinical trial information: NCT04095221. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: JCO Oncology Practice, American Society of Clinical Oncology (ASCO), Vol. 18, No. 3 ( 2022-03), p. 224-231
    Abstract: Adolescents and young adults (AYAs; age 15-39 years) with cancer are under-represented in cancer clinical trials because of patient, provider, and institutional barriers. Health care technology is increasingly available to and highly used among AYAs and has the potential to improve cancer care delivery. The COVID-19 pandemic forced institutions to rapidly adopt novel approaches for enrollment and monitoring of patients on cancer clinical trials, many of which have the potential for improving AYA trial participation overall. This consensus statement from the Children's Oncology Group AYA Oncology Discipline Committee reviews opportunities to use technology to optimize AYA trial enrollment and study conduct, as well as considerations for widespread implementation of these practices. The use of remote patient eligibility screening, electronic informed consent, virtual tumor boards, remote study visits, and remote patient monitoring are recommended to increase AYA access to trials and decrease the burden of participation. Widespread adoption of these strategies will require new policies focusing on reimbursement for telehealth, license portability, facile communication between electronic health record systems and advanced safeguards to maintain patient privacy and security. Studies are needed to determine optimal approaches to further incorporate technology at every stage of the clinical trial process, from enrollment through study completion.
    Type of Medium: Online Resource
    ISSN: 2688-1527 , 2688-1535
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 3005549-0
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  • 8
    In: Cancer, Wiley, Vol. 120, No. 13 ( 2014-07), p. 1985-1992
    Abstract: Outpatient intravenous antibiotic prophylaxis reduces the incidence of clinically or microbiologically documented infection and bacteremia, especially viridans streptococcal bacteremia, in children receiving treatment for acute myeloid leukemia. However, vancomycin‐resistant enterococcal bacteremia has been documented in patients receiving antibiotic prophylaxis, and approaches to minimize resistance should be explored.
    Type of Medium: Online Resource
    ISSN: 0008-543X , 1097-0142
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1479932-7
    detail.hit.zdb_id: 2599218-1
    detail.hit.zdb_id: 2594979-2
    detail.hit.zdb_id: 1429-1
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  • 9
    In: Current Problems in Cancer, Elsevier BV, ( 2022-9), p. 100898-
    Type of Medium: Online Resource
    ISSN: 0147-0272
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2022907-0
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  • 10
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 11 ( 2023-06-01), p. 2043-2051
    Abstract: Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes. Patients and Methods: This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1. Results: Thirty patients were enrolled [60% male; median age 54 years (range, 24–78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%–17.2%] . The median PFS was 7.6 weeks (two-sided 95% CI, 6.9–26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway–related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline. Conclusions: Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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