PD1 inhibition in soft-tissue sarcomas with tertiary lymphoid structures: A multicenter phase II trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11507-11507
Author(s):  
Antoine Italiano ◽  
Alban Bessede ◽  
Emmanuelle Bompas ◽  
Sophie Piperno-Neumann ◽  
Christine Chevreau ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Soft Tissue ◽  
Phase Ii ◽  
Progressive Disease ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Progression Rate ◽  
Multicenter Phase ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

11507 Background: PD1 inhibition has shown limited activity in all comers clinical trials including patients with advanced soft-tissue sarcomas (STS). In the PEMBROSARC study, objective response rate, progression-free (PFS) and overall survival (OS) were respectively 2.1%, 1.4 and 7.1 months respectively (Toulmonde et al. Jama Oncol 2017). We have recently shown that the presence of tertiary lymphoid structures (TLS) may represent a biomarker to select patients who are more likely to benefit from immunotherapy (PetitPrez et al., Nature 2020). We report here the first clinical trial investigating the efficacy of PD1 inhibition in TLS-positive STS. Methods: PEMBROSARC is an open-label multicenter phase II study of pembrolizumab in combination with low-dose cyclophosphamide in pts with STS selected based on the presence of TLS. TLS status has been assessed centrally has previously described (PetitPrez et al., Nature 2020). Eligible patients received pembrolizumab 200mg IV q21 days and cyclophosphamide 50 mg BID 1week on, 1 week off. All patients had confirmed progressive disease at inclusion based on central review of two imaging performed at less than 6 months interval. The primary efficacy endpoint was 6-month non-progression (as per RECIST evaluation criteria v1.1). Based on the following hypotheses: 15% 6-month non-progression rate (H0), 40% acceptable 6-month non-progression rate (H1), 5% type I error rate, 90% power, a total of 29 assessable patients were necessary and 8 patients or more had to be progression-free at 6 months to reach the first endpoint. Results: 240 patients were screened for TLS status between September 2018 and January 2020 in 7 centers of the French Sarcoma Group. Among them, 48 were found to be TLS+ as per central review and 35 were included in the study. The three most frequent histological subtypes were: well-differentiated/dedifferentiated liposarcoma (n = 13); UPS (n = 6), and leiomyosarcoma (n = 4). 30 patients were eligible for efficacy. Of those, as per central imaging review, 13 patients (43.3%) had tumor shrinkage resulting in partial response in 8 patients (26.7%) and stable disease in 5 cases (16.7%). 10 patients had progressive disease. Twelve patients were progression-free at 6 months (40.0% 95%CI = [22.7 – 59.4]).Median PFS and OS were 4.1 months (95%CI, 1.4-9.6) and 14.5 months (95%CI, 8.5- 18.3 months), respectively. Conclusions: With an objective response and a 6-month non-progression rates of 26.7% and 40% respectively versus 2.1% and 4.2% in all comers, the PEMBROSARC study confirms that selection based on TLS status is an efficient approach to tailor immunotherapy in STS patients. Clinical trial information: NCT02406781.

A randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition in metastatic soft tissue sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11583-TPS11583
Author(s):  
Vanessa Anne Eulo ◽  
Breelyn A. Wilky ◽  
Jingqin Luo ◽  
Angela C. Hirbe ◽  
Mia C. Weiss ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Soft Tissue ◽  
Phase Ii ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Randomized Phase Ii ◽  
Metastatic Setting

TPS11583 Background: Soft tissue sarcomas (STS) are rare malignancies with poor prognosis in the metastatic setting. Current standard therapy includes anthracycline based chemotherapy. Cabozantinib is a multikinase inhibitor that has demonstrated efficacy in solid tumors such as renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). A phase II study of cabozantinib in advanced STS is underway. Cabozantinib in combination with immune checkpoint blockade has shown clinical benefit in several tumor types including HCC, RCC, non-small cell lung cancer, and urothelial carcinoma. Since cabozantinib may alter PD-1 expression in regulatory T-cells and promote an immune permissive environment, we hypothesize that combining cabozantinib with immune checkpoint inhibition is a therapeutic strategy that will be more effective than cabozantinib alone. Additionally, the design of the trial will allow assessment of whether pretreatment with cabozantinib will enhance the efficacy of nivolumab and ipilimumab alone. Methods: This is an open label, multicenter, randomized phase II clinical trial of cabozantinib (60mg orally daily as a single agent, 40mg in combination) with or without combination Ipilimumab (ipi, 1mg/kg IV every 3 weeks for 4 doses) and Nivolumab (nivo, 3mg/kg IV every 3 weeks for four doses, then 480mg IV every 4 weeks) in patients (pts) with unresectable or metastatic STS refractory to up to two lines of chemotherapy. 105 pts with non-translocation driven sarcomas will be enrolled at three US sites and randomized 2:1 to the combination group. Pts will be stratified by prior pazopanib use and balanced for histologies. Patients who progress on arm A will cross over to combination therapy (arm B). The primary efficacy endpoint is objective response rate (ORR) by RECIST 1.1. 35 patients in Cohort A (cabozantinib alone) and 70 patients in Cohort B (cabozantinib plus ipi/nivo) will be required to detect an increase of the ORR from 10% in cohort A to 30% in cohort B with 81% power with a one-sided alpha level of 10%. Key eligibility criteria include: at least 18 years of age, ECOG performance status of 0 or 1, ≤2 prior lines of therapy and measurable disease. Exclusion criteria include: translocation-driven sarcoma except alveolar soft part sarcoma (ASPS), prior immunotherapy, and chronic use of corticosteroids or other immunosuppression. Secondary endpoints are safety, overall and progression free survival, disease control rate, and response rate to ipilimumab and nivolumab after cabozantinib pretreatment. Mandatory tumor biopsies pre-treatment and at 6 weeks will be obtained. Peripheral blood will be collected for circulating immune phenotyping. Enrollment will occur at 3 participating institutions and is expected to be completed in 2022. Clinical trial information: NCT04551430.

A randomized phase II study of durvalumab and tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma (MEDISARC, AIO-STS 0415).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS11075-TPS11075
Author(s):  
Viktor Grünwald ◽  
Sebastian Bauer ◽  
Barbara Hermes ◽  
Philipp Ivanyi ◽  
Lars H Lindner ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Soft Tissue ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Soft Tissue Sarcomas ◽  
Predictive Biomarkers ◽  
Ecog Performance Status ◽  
Curative Intent

TPS11075 Background: Soft tissue sarcomas (STS) are rare tumors and exhibit substantial histological diversity. Efficacious targeted 1st line treatment for advanced or metastatic STS is not available, and the standard therapy has been anthracycline-based for decades. This strategy shows poor efficacy, as demonstrated by a median Overall Survival (OS) of 12-20 months. Several STS subtypes, however, have been shown to express PD-L1, and immune checkpoint inhibitors (ICI) have demonstrated principle anti-tumor activity in pretreated STS. Our ongoing clinical trial tests the activity and safety of ICI combination therapy in the first-line setting. We hypothesize that the dual checkpoint blockade with Durvalumab (PD-L1) and Tremelimumab (CTLA-4) improves overall survival in STS when compared to the standard of care doxorubicin. Methods: MEDISARC is a multi-center phase II trial that is enrolling adult treatment-naïve patients with histologically confirmed STS of intermediate or high grade (FNCLCC grade 2 or 3) not amenable to surgery with curative intent and ECOG performance status 0-2. Chemosensitive histologic STS are eligible. 100 patients will be randomized 1:1, stratified by ECOG status (0 vs. 1/2). Patients in the experimental arm are treated with fixed doses of durvalumab (1.5 g Q4W) and tremelimumab (75 mg Q4W for 3 cycles, then Q12W) until Progressive Disease (PD) or for a maximum of 12 months. Doxorubicin treatment in the standard arm is at 75 mg/m2 Q3W and limited to 6 cycles. OS is the primary endpoint. Secondary endpoints include 2-year OS rate, PFS, ORR according to conventional and modified RECIST 1.1, safety and tolerability and health-related quality of life (EORTC QLQ-C30). OS analysis may be performed when the required number of events (E=70) has been observed. All randomized and treated subjects will be included in the efficacy and safety analysis. The accompanying translational research aims to identify prognostic and predictive biomarkers in blood and tumor tissue. Enrollment of patients started in April 2018 and is ongoing. As of February 2019, 32 patients have been enrolled. The study is sponsored by AIO-Studien-gGmbH, Berlin, Germany. Clinical trial information: 2016-004750-15.

TiFFANY study: A multicenter phase II basket-type clinical trial to evaluate efficacy and safety of pan-FGFR inhibitor TAS-120 for advanced solid malignancies with FGFR alterations identified by circulating tumor DNA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3156-TPS3156
Author(s):  
Tomoko Jogo ◽  
Yoshiaki Nakamura ◽  
Yoshito Komatsu ◽  
Ken Kato ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Survival Duration ◽  
Efficacy And Safety ◽  
Multicenter Phase ◽  
Solid Malignancies ◽  
Ctdna Analysis ◽  
Tumor Dna

TPS3156 Background: Approximately 7% of advanced solid malignancies have FGFR gene alterations. However, standard treatment for FGFR-altered malignancies has not been established. Moreover, circulating tumor DNA (ctDNA) analysis has a potential to accurately identify FGFR alterations by assessing spatial and temporal intratumoral heterogeneity, which have shown to be associated with a poor prognosis and resistance to anti-cancer therapy. Methods: We are conducting an investigator-initiated multicenter phase II basket-type trial to investigate efficacy and safety of TAS-120, a highly selective covalent pan-FGFR inhibitor, for the patients with advanced solid malignancies with FGFR alterations identified by ctDNA analysis as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). Eligibility criteria include histologically confirmed unresectable advanced or recurrent solid tumors regardless of histology of origin; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and clonal FGFR alterations ( FGFR1-3 gain-of-function mutations, FGFR1,2 amplifications and FGFR2,3 fusions) identified by a 73-gene sequencing ctDNA panel (Guardant360). Enrolled patients will receive TAS-120 20 mg once daily, orally, in a 21 day-cycle. The primary endpoint is to clarify objective response rate (ORR) assessed by investigators per RECIST v1.1. The secondary endpoints are to evaluate progression-free survival, duration of response, time to treatment failure, disease control rate, overall survival, ORR by central determination, and incidence of adverse events. Target sample size is determined as 26 to test the null hypothesis of ORR as 5% with one-sided alpha level of 2.5% and power of 80% to detect an expected value of ORR as 25%. Furthermore, tumor tissue and ctDNA will be serially collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. Clinical trial information: 194624.

scholarly journals Phase II Trial of Dolastatin-10, a Novel Anti-Tubulin Agent, in Metastatic Soft Tissue Sarcomas

Sarcoma ◽  
2004 ◽  
Vol 8 (4) ◽  
pp. 107-111 ◽  
Author(s):  
M. von Mehren ◽  
S. P. Balcerzak ◽  
A. S. Kraft ◽  
J. H. Edmonson ◽  
S. H. Okuno ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Hematological Toxicity ◽  
The Novel ◽  
Version 2.0 ◽  
Tumor Measurements ◽  
Dolastatin 10

Patients:Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting.Methods:Dol-10 was given intravenously at a dose of 400 μg/m2and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al.Cancer1981; 47(1): 207].Results:Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10.Discussion:Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas.

Phase I trial of dacarbazine and bortezomib in melanoma and soft tissue sarcoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 18008-18008 ◽  
Author(s):  
J. D. Roberts ◽  
M. S. Ernstoff ◽  
C. Birdsell
Keyword(s):  
Soft Tissue ◽  
Phase Ii ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Single Agent ◽  
Soft Tissue Sarcomas ◽  
Primary Objective ◽  
Anticancer Effects ◽  
Melanoma Patients ◽  
Related Agent

18008 Background: Dacarbazine (D) has modest single agent activity against melanoma and soft tissue sarcomas. NFκB is a transcription factor that in general promotes cell survival and antagonizes apoptosis. In melanoma NFκB is constitutively activated and increases further in response to D. Bortezomib (B) is a prosteasome inhibitor that down-regulates NFκB. In tissue culture and xenograft melanoma models B potentiates anticancer effects of D and the related agent temozolomide. Methods: The primary objective is to identify recommended phase II doses for D+B administered weekly. Patients with advanced melanoma or sarcoma are enrolled in a traditional ‘3+3‘ dose escalation format. Results: Recommended phase II doses will be at least D 250 mg/m2 and B 1.6 mg/m2, and dose escalation continues. Treatment has been generally well tolerated with known D and B toxicities. Among 8 melanoma patients there is 1 partial response (PR), 1 with stable disease on treatment 15 weeks, 6 with progressive disease (PD) 6, 7, 8, 8, 13, and 13 weeks. Among 5 sarcoma patients there is 1 PR and 4 with PD 4, 8, 16, and 24 wks. Conclusions: At full dose B and moderate dose D for this schedule, D+B is feasible and generally well-tolerated. Activity beyond that of D alone is not apparent to date, but several or all patients have been treated at less than maximum tolerated doses. [Table: see text]

Multicenter Phase II Clinical Trial of Nilotinib for Patients with Imatinib-Resistant or Intolerant CML From the East Japan CML Study Group (EJCML) Trial: Evaluation of Molecular Responses by the BCR-ABL1 Mutational Status and Plasma Trough Concentration of Nilotinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1360-1360 ◽  
Author(s):  
Naoto Takahashi ◽  
Masatomo Miura ◽  
Jun Kuroki ◽  
Kinuko Mitani ◽  
Atsushi Kitabayashi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Phase Ii ◽  
Trough Concentration ◽  
Progressive Disease ◽  
Study Group ◽  
Molecular Responses ◽  
Multicenter Phase ◽  
Mutational Status ◽  
Imatinib Resistant

Abstract Abstract 1360 Introduction: The tyrosine kinase inhibitor (TKI) imatinib is used as the first-line therapy for newly diagnosed chronic myeloid leukemia (CML). However, some patients fail to respond or become intolerant to imatinib. Nilotinib is a second-generation TKI with higher selectivity and more potent inhibitory effects on BCR-ABL than imatinib. Several studies have shown hematologic and cytogenetic responses to nilotinib in patients with imatinib-resistant or intolerant CML. Purpose: To investigate the safety and efficacy of nilotinib for patients with imatinib-resistant or intolerant, chronic (CP)- or accelerated (AP)-phase CML from the East Japan CML Study Group (EJCML) trial by evaluating molecular responses in terms of the BCR-ABL1 mutational status and plasma trough concentration of nilotinib. Methods: In this multicenter phase II clinical trial, nilotinib (400 mg bid) was administered orally for one year and the molecular responses were monitored by means of the international scale of quantitative PCR (IS-PCR). BCR-ABL1 mutations were analyzed by direct sequencing at the baseline and 12 months or at the time of the event for discontinuation of the treatment (i.e., progressive disease, insufficient effects, or severe adverse events). The plasma trough concentration of nilotinib was measured by high-performance liquid chromatography 3 months after nilotinib administration. Results: From March 2009 through February 2011, 51 patients were registered in this study, and data of 49 patients whose molecular responses were evaluated by the IS-PCR were analyzed (imatinib-resistant CML = 33, imatinib-intolerant CML = 16; CP CML = 46, AP CML = 3). The median follow-up period was 12.0 months (range = 0.1–13.3 months). At 6 and 12 months, the major molecular response (MMR; ≤0.1% IS) rates were 52.5% and 67.6%, respectively, and the complete cytogenetic response (CCyR)-equivalent (≤1.0% IS) rates were 75.0% and 85.3%, respectively. Five types of BCR-ABL1 mutations (M244V, F317L, N358D, F359V, and E459K) were detected in 6 patients (12.2%) at the baseline, but the M244V, N358D, and E459K mutations disappeared after the nilotinib treatment. Acquired BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35bp insertion) were detected in 3 patients (8.6%) at 12 months or at the time of the event; these patients did not achieve a CCyR or an MMR. No patients showed an acquired mutation of T315I. Most patients except 11 subjects (22.4%) still received the treatment. The reasons for discontinuation were progressive disease in one patient with an F317L mutation, insufficient effects in one patient without any mutation, and adverse events in 9 patients (thrombocytopenia in 5 patients, hyperbilirubinemia in 2 patients, headache in one patient, and heart disease in one patient). Among 30 patients without BCR-ABL1 mutations, the plasma trough concentration of nilotinib was significantly higher in 21 patients with an MMR than in those without an MMR by 12 months (median = 1255.1 ng/mL vs. 372.8 ng/mL, P = 0.0012 by Mann–Whitney U-test; see the figure). The concentration of 761 ng/mL was significantly associated with an MMR by 12 months in a receiver-operating characteristic (ROC) curve analysis of the best sensitivity (76.2%) and specificity (77.8%). Conclusion: The patients with imatinib-resistant or intolerant, CP or AP CML, even those having BCR-ABL1 mutations M244V, N358D, and E459K, achieved an MMR by 12 months of nilotinib treatment. The plasma trough concentration of the drug was related to the MMR by 12 months, and the plasma threshold of nilotinib should be set above 761 ng/mL. These findings suggest that nilotinib shows good efficacy and tolerability in Japanese patients with imatinib-resistant or intolerant, CP or AP CML. (ClicalTrials.gov, UMIN ID 000002201) Disclosures: No relevant conflicts of interest to declare.

Multicenter phase II study of everolimus in patients with metastatic or recurrent bone and soft-tissue sarcomas after failure of anthracycline and ifosfamide

2013 ◽  
Vol 31 (6) ◽  
pp. 1602-1608 ◽  
Author(s):  
Changhoon Yoo ◽  
Jeeyun Lee ◽  
Sun Young Rha ◽  
Kyong Hwa Park ◽  
Tae Min Kim ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Soft Tissue Sarcomas ◽  
Multicenter Phase

Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002

2007 ◽  
Vol 25 (19) ◽  
pp. 2755-2763 ◽  
Author(s):  
Robert G. Maki ◽  
J. Kyle Wathen ◽  
Shreyaskumar R. Patel ◽  
Dennis A. Priebat ◽  
Scott H. Okuno ◽  
...  
Keyword(s):  
Overall Survival ◽  
Soft Tissue ◽  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Fixed Dose ◽  
Open Label ◽  
Adaptive Randomization ◽  
Number Of Patients

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

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