Results of a randomized phase II/III study comparing perioperative adriamycin plus ifosfamide and gemcitabine plus docetaxel for high-grade soft tissue sarcomas: Japan Clinical Oncology Group study JCOG1306.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11504-11504 ◽  
Author(s):  
Kazuhiro Tanaka ◽  
Ryunosuke Machida ◽  
Akira Kawai ◽  
Robert Nakayama ◽  
Satoshi Tsukushi ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Febrile Neutropenia ◽  
Phase Ii ◽  
Interim Analysis ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Point Estimate ◽  
High Grade ◽  
Standard Regimen

11504 Background: Our previous phase II study for high-grade soft tissue sarcomas (STS), JCOG0304, suggested long-term favorable effects of perioperative adriamycin plus ifosfamide (AI) on survival of STS patients. We have also reported in 2015 ASCO Annual Meeting that a phase II/III trial to confirm the non-inferiority of perioperative gemcitabine plus docetaxel (GD) to AI for high-grade STS (JCOG1306) had been started. We herein report the results of JCOG1306 at the early termination by the preplanned second interim analysis. Methods: Patients with operable, FNCLCC grade 2/3 STS primary tumor (T2bN0M0 or anyTN1M0, AJCC 7th edition) or first local recurrent tumor in the extremities or trunk were randomized to AI or GD. Chemotherapy consisted of adriamycin 60 mg/m2 plus ifosfamide 10 g/m2 for AI or gemcitabine 1,800 mg/m2 plus docetaxel 70 mg/m2 for GD. The treatments were repeated for 3 courses preoperatively and 2 courses postoperatively in a 3-week interval. The primary endpoint in phase III part was overall survival (OS). Planned sample size was 140 with a one-sided alpha of 0.1, power of 0.7 and a non-inferiority margin of 8% at 3-year OS, assuming 3-year OS of AI to be 85% and that of GD as 87%. The patient accrual has started in February 2014 and finished in September 2018. Results: A total of 143 patients were enrolled and included in the efficacy analysis. Seventy and 73 patients were assigned to AI and GD, respectively. At the second interim-analysis on December 2019, the estimated 2-year OS was 94.3 % (95% confidence interval (CI) 83.4–98.1) in AI and 91.6 % (80.9–96.4) in GD (hazard ratio (HR) 2.55, 95% CI 0.67–9.78). The estimated 2-year progression-free survival was 81.9 % (95% CI: 69.5–89.7) in AI and 64.0 % (51.1–74.4) in GD (HR 2.32, 95% CI 1.22–4.39). There were no treatment-related deaths in both groups. The most common Grade 3 or higher adverse events in AI were neutropenia (88.4%), anemia (49.3%), and febrile neutropenia (36.2%), whereas those in GD were neutropenia (79.5%), febrile neutropenia (17.8%), and alanine aminotransferase (9.6%). Based on the result of this analysis, the Data Monitoring and Safety Committee of JCOG recommended terminating the study since the point estimate of HR was above the pre-specified allowable HR of 1.61. Conclusions: Although the toxicities were modest in GD, non-inferiority of GD to AI could not be confirmed. In the perioperative chemotherapy for high-grade STS in the extremities and trunk, AI remains the standard regimen. Clinical trial information: UMIN000013175 .

scholarly journals Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials

2020 ◽  
Vol 10 ◽  
Author(s):  
Pierre-Yves Cren ◽  
Loïc Lebellec ◽  
Thomas Ryckewaert ◽  
Nicolas Penel
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Multikinase Inhibitors ◽  
Randomized Phase Ii ◽  
Phase Iii Trials

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

Phase II study of the A-ICOX regimen [bevacizumab (Bev), weekly intermittent capecitabine (Cap) and oxaliplatin (Ox)] for untreated advanced colorectal cancer (CRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4092-4092
Author(s):  
R. K. Ramanathan ◽  
K. Rajasenan ◽  
T. Crandall ◽  
E. P. Balaban ◽  
R. A. Pinkerton ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Phase Iii ◽  
Rank Test ◽  
Hematological Toxicity ◽  
Ecog Performance Status ◽  
Standard Regimen ◽  
Hand Foot Syndrome

4092 Background: FOLFOX in combination with Bev is a standard regimen for treating advanced CRC. Cap on a d 1–14 schedule every 3 weeks is now being substituted for 5-flurouracil (CapOx); however optimal doses and schedules of Cap in combination with Ox and Bev needs continued evaluation. Intermittent weekly Cap (3,500 mg/m2, d 1–7) with Ox (85 mg/m2) every 2 weeks compared to the standard CapOx regimen in untreated advanced CRC has shown superior response and time-to-progression in Europe (Scheithauer W et al. J Clin Oncol. 21,1307; 2003). Methods: This phase II trial is designed to evaluate the A-ICOX regimen in US patients with CRC. The primary endpoint is to detect a 50% improvement in median progression free survival (PFS) from 8 to 12 months. With a sample of 40 patients, a 1-sided level 0.1 log-rank test has 81% power to detect this difference. Patients with advanced untreated CRC are eligible for study. Cap is administered at the dose of 2,500 mg/m2 in two divided doses on d 1–7 (n=11) and has been increased to 3000 mg/m2 dose (n=26), based on tolerability of the lower dose. The dose of Ox is 85 mg/m2 and Bev is 5 mg/kg. Cycles are repeated every 2 weeks. Results: Thirty-seven of 40 pts have been enrolled, with 30 evaluable for toxicity and response. Patient characteristics: Male (n=19); ECOG performance status 0 (n=18), 1 (n=12); median age 63 (range 38–80 years). Median cycles administered 4 (range 1–17). Partial responses were seen in 10 pts (33%), and metastasectomy was performed in 8 pts (27%). The PFS analysis is premature at this point. Gr 3/4 hematological toxicity occurred in only 2 pts (7 %). Other gr 3/4 adverse events have included: diarrhea (10 %), hand-foot syndrome (7 %), peripheral neuropathy (7%), nausea (7%) and vomiting (7 %). Conclusions: The first US experience of the A-ICOX regimen shows it to be very well tolerated, and Cap (3,000 mg/m2, d 1–7) in combination with Ox and Bev therapy can be safely administered. The incidence of subsequent metastasectomy, a marker of activity, is encouraging. A phase III trial of the A-ICOX regimen is now being conducted against standard Q-3 weekly CapOx/Bev. (Study supported by Genentech and Roche Pharmaceuticals) [Table: see text]

A phase II trial of modified gemcitabine plus S-1 combination as the first-line treatment in patients with advanced biliary tract cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 417-417
Author(s):  
Nai-Jung Chiang ◽  
Jen-Shi Chen ◽  
Ming-Huang Chen ◽  
Shih-Hung Yang ◽  
Chiun Hsu ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Phase Ii ◽  
Biliary Tract Cancer ◽  
Null Hypothesis ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Standard Regimen ◽  
Tract Cancer ◽  
To Receive

417 Background: Gemcitabine plus platinum, notably cisplatin, is conceived as the standard regimen for advanced biliary tract cancer (ABTC) nowadays. Recent randomized phase II study (JCOG0805) showed that gemcitabine plus S-1 was more promising than S-1 alone in ABTC, and a randomized phase III, UMIN 000001685, is currently ongoing to compare the efficacy of gemcitabine plus either S-1 (GS) or cisplatin (GC) in ABTC. Herein, we report the results of a single arm phase II of modified GS in Taiwanese ABTC patients, NCT02425137. Methods: Patients with chemonaïve ABTC were eligible to receive 800mg/m2 gemcitabine with 10 mg/m2/min infusion, on day 1 plus daily 80/100/120 mg of S-1 (based on BSA) days 1-10, in a 2-week cycle. With Optimal Simon’s two-stage design and (p0= 0.4, p1= 0.6) for 12-week disease control rate (proportion of patients with complete or partial response [CR/PR] or stable disease ≥ 12 weeks [SD≥ 12weeks]) and given error probabilities (alpha = 0.05, beta = 0.2), the null hypothesis (p0) would be rejected if 24 or more patients with CR/PR/SD≥ 12weeks were observed among 46 accruals. Tumor response was assessed by CT/MRI every 6 weeks according to RECIST v1.1. Results: Between May 2015 and April 2016, totally 46 evaluable patients were enrolled to receive a median of 9.5 cycles (range: 3-31) of modified GS. After a median of 8.7 months (95% CI, 6.7-9.1) follow-up, 10 (21.7%) patients achieved PR and additional 23 (50%) had SD>12weeks. The median progression-free survival and overall survival was 5.6 (95% CI, 4.4-7.2) and 10.8 (95% CI, 7.6-not reached) months, respectively. All grade 3 treatment-related AEs were < 5%. The dose intensity of S-1 and gemcitabine were both more than 95%. Conclusions: By the observation of 33 patients with PR/SD≥ 12weeks, the null hypothesis was rejected. Modified GS is an active regimen with excellent safety profiles and deserves further investigation for the management of Asian ABTC patients. Clinical trial information: NCT 02425137.

Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas

2012 ◽  
Vol 30 (1) ◽  
pp. 78-84 ◽  
Author(s):  
Sant P. Chawla ◽  
Arthur P. Staddon ◽  
Laurence H. Baker ◽  
Scott M. Schuetze ◽  
Anthony W. Tolcher ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase Ii ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Soft Tissue Sarcomas ◽  
Phase Iii ◽  
Target Of Rapamycin ◽  
Mucosal Inflammation ◽  
Spindle Cell Sarcoma ◽  
Open Label

PurposeRidaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas.Patients and MethodsPatients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated.ResultsA total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue.ConclusionSingle-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.

scholarly journals Phase II study of concomitant radiotherapy with atezolizumab in oligometastatic soft tissue sarcomas: STEREOSARC trial protocol

BMJ Open ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. e038391
Author(s):  
Jennifer le Guevelou ◽  
Colin Debaigt ◽  
Esma Saada-Bouzid ◽  
Julien Viotti ◽  
Nazim Khalladi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Soft Tissue ◽  
Phase Ii ◽  
Tumour Response ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Primary Objective ◽  
National Agency ◽  
Health Products ◽  
Scientific Meetings

IntroductionUp to 50% of soft tissue sarcoma (STS) patients develop metastases in the course of their disease. Cytotoxic therapy is a standard treatment in this setting but yields average tumour response rates of 25% at first line and ≤10% at later lines. In oligometastatic stage, stereotactic body radiation therapy (SBRT) allows reaching high control rates at treated sites (≥80%) and is potentially equally effective to surgery in term of overall survival. In order to shift the balance towards antitumour immunity by multisite irradiation, radiation could be combined with inhibitors of the immunosuppressive pathways.Methods and analysisSTEREOSARC is a prospective, multicentric, randomised phase II, designed to evaluate the efficacy of SBRT associated with immunotherapy versus SBRT only. Randomisation is performed with a 2:1 ratio within two arms. The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic multisite irradiation in oligometastatic sarcoma patients. The secondary objectives include PFS by immune response criteria, overall survival, quality-of-life evaluation and developing mathematical models of tumour growth and dissemination predictive of oligometastatic versus polymetastatic evolution. Patients will be randomised in two groups: SBRT with atezolizumab and SBRT alone. The total number of included patients should be 103.Trial registrationThe trial is registered on ClinicalTrials.gov (ID: NCT03548428).Ethics and disseminationThis study has been approved by Comité de Protection des Personnes du sud-ouest et outre-mer 4 on 18 October 2019 (Reference CPP2019-09-076-PP) and from National Agency for Medical and Health products Safety (Reference: MEDAECNAT-2019-08-00004_2017-004239-35) on 18 September 2019.The results will be disseminated to patients upon individual request or through media release from scientific meetings. The results will be communicated through scientific meetings and publications.

scholarly journals Phase II Trial of Doxorubicin Plus Escalated High-Dose Ifosfamide in Patients With Advanced Soft Tissue Sarcomas of the Adult: A Study of the Spanish Group for Research on Sarcomas (GEIS)

Sarcoma ◽  
2006 ◽  
Vol 2006 ◽  
pp. 1-8 ◽  
Author(s):  
A. López-Pousa ◽  
J. Martín ◽  
J. Montalar ◽  
R. de las Peñas ◽  
J. García del Muro ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Febrile Neutropenia ◽  
Continuous Infusion ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Soft Tissue Sarcomas ◽  
High Dose ◽  
Substantial Toxicity ◽  
Grade 3

Background.To explore the tolerance and the activity of high-dose ifosfamide (IFOS) combined with doxorubicin (DXR) at 50 mg/m2every 4 weeks in patients with soft tissue sarcomas.Methods.DXR was given IV bolus and IFOS by continuous infusion at 2 g/m2/day. Initial IFOS dose (12 g/m2) was adjusted to 10, 13, or 14 g/m2according to toxicity.Results.Seventy patients received 277 cycles (median 3 cycles, range 1–10), 34% with IFOS dose increased, 30% decreased, and 48% delivered at 12 g/m2. Toxicity grade 4 occurred on granulocytes (67% of patients) or platelets (19%), 54% had febrile neutropenia, 31% grade 3/4 asthenia, and 26% abandoned the study due to toxicity. Three toxic deaths occurred. In 57 non-GIST patients objective activity was 45.6% (95% CI, 32 to 58%).Conclusion.At least 4 cycles were tolerated by 71% of patients, most receiving DXR 50 mg/m2plus IFOS 10–12 g/m2, with substantial toxicity.

scholarly journals Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial

2020 ◽  
Vol 8 (2) ◽  
pp. e001561
Author(s):  
Javier Martin-Broto ◽  
Nadia Hindi ◽  
Giovanni Grignani ◽  
Javier Martinez-Trufero ◽  
Andres Redondo ◽  
...  
Keyword(s):  
Survival Rate ◽  
Soft Tissue ◽  
Phase Ii ◽  
Evaluation Criteria ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Recommended Dose ◽  
Free Survival ◽  
Phase Ib ◽  
Inhibition Of Angiogenesis

BackgroundSarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).MethodsThis single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level −1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).ResultsFrom May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4–26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3–4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).ConclusionsSunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months.Trial registration numberNCT03277924.

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