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Gastrointestinal Stromal Tumors

Disease Attributes

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Quality of Life

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Maintenance of Imatinib at the last dose routinely taken by the patient in the 3 years period prior to randomization (either 300 or 400 mg/day). Increase dose up to 800 mg/day if relapse according to RECIST 1.1 criteria. Any relapse/progressive disease at 800 mg/day will lead to Imatinib permanent discontinuation and study discontinuation. In case of toxicity, Imatinib dose will be interrupted or adjusted in accordance with Imatinib Specific Product Characteristics (SPC).

Treatment corresponding to standard practice : interruption of Imatinib from the day of randomization. Reintroduction of Imatinib at 400 mg/day after first relapse according to RECIST 1.1 criteria; Then increase dose to 800 mg/day after 2d relapse. Any relapse/progressive disease at 800 mg/day will lead to Imatinib permanent discontinuation and study discontinuation. In case of toxicity, Imatinib dose will be interrupted or adjusted in accordance with Imatinib SPC.

Either 300 or 400 mg/day in accordance with the last dose routinely taken by the patient in the 3-year period before randomization. The treatment will be orally taken at time of meal with a large glass of water

Imatinib maintenance

Jean-Yves Blay, Pr

This is a 2 arms study concerning patients with primary GIST who followed an Imatinib adjuvant treatment for 3 years after surgery and who have a high risk of recurrence.

In the first arm, patients will continue Imatinib treatment for 3 more years, allowing to determine if the continuation of this treatment is efficient for disease control, in terms of Disease Free Survival improvement.

In the second arm, patients will discontinue the Imatinib treatment, as standard practice. This arm will allow to determine if the re-introduction of Imatinib at relapse is still an efficient treatment for the control of disease.

Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms, mostly diagnosed between 55 and 60 years of age, which account for 5% of all sarcomas. Worldwide annual incidence is approximately 12 cases per million people, corresponding to approximately 800 new cases per year in France.

A large majority of GISTs harbour activating mutations in the proto-oncogenes KIT and/or PDGFRA, both coding cell-surface cytokine receptors with tyrosine-protein kinase activity.

Imatinib mesilate (Glivec®, Novartis Pharma SAS) is a selective tyrosine kinase inhibitor, leading to inhibition of KIT and PDGFRA signalling pathways. The introduction of imatinib has revolutionised the therapeutic management of GIST patients and has provided an unprecedented demonstration of the clinical benefit of a targeted therapy for patients with advanced/metastatic solid tumors. First results from prospective trials conducted with imatinib in GIST patients have demonstrated a 300% increase in median overall survival, and a likely 100% increase in 5 and 10-year survival as compared to cytotoxic chemotherapy.

The successful use of imatinib in the treatment of advanced GISTs and the significant risk of recurrence of advanced GISTs have prompted the investigation of the clinical benefit of imatinib as a post-operative adjuvant therapy. Two prospective randomized Phase III trials have demonstrated that adjuvant imatinib treatment significantly prolong overall survival (OS) and recurrence-free survival (RFS) when given for 3 years. To date, imatinib is also indicated in the adjuvant setting after complete resection of primary, localized, KIT-positive GIST at high risk of recurrence. However, the optimal treatment duration remains unclear and it should be determined whether

1. prolonged use of adjuvant imatinib beyond 3 years may enable to reduce the risk of GIST recurrence and to improve overall survival, and
2. imatinib rechallenge is efficient for treating recurrence after completion of 3-year adjuvant imatinib therapy.

This trial is an open-label, randomized, multicenter phase III study aiming to determine the clinical impact of maintaining imatinib treatment beyond 3 years in the adjuvant setting for patients with resected GISTs at high risk of recurrence according to the National Comprehensive Cancer Network Task Force on GIST (NCCN) risk classification.

Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)

A Randomized Multicenter Phase III Trial Evaluating the Interest of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)

Time from the date of randomisation to the first documented relapse or death due to any cause. Patients with no event at the time of analysis will be censored at the date of the last adequate tumour assessment. The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

Time from the date of randomization until the date of death due to any cause and censored at the date of last contact for patients alive at last contact. The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

Time from the date of randomization until the date of first relapse under Imatinib treatment (i.e first relapse in the "Imatinib maintenance arm" and relapse after reintroduction of Imatinib in the "Interruption of Imatinib arm"). The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

Percentage of patients in Complete Response (CR) after reintroduction of Imatinib treatment for patients assigned to the interruption arm and who experience GIST recurrence. CR is assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

The assessment of safety will be based mainly on the frequency of AE based on the Common Toxicity Criteria version 4 grade. AE will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. Patients with at least either one serious AE, or one grade 3-4, or one AE requiring the interruption of study treatment, will be described by study arm and compared using a Pearson's Chi2 test or a Fisher's exact test, if adequate. Patients will be analyzed according the duration of exposure to imatinib

QoL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire (QLQ-C30). Descriptive statistics (e.g. means and medians) will be used to summarize the scored scales at it scheduled assessment time point of the questionnaire. The distribution of time to definitive health-related QoL deterioration by study arms will be estimated using the Kaplan-Meier method. The time to definitive deterioration is defined as the time from the date of randomization to the date of event, wich is defined as \> 10 points decrease from baseline of QLQ-C30 global score (items 29 and 30) or death due to any cause. If patient has not had an event, time to QoL deterioration will be censored at the date of last adequate evaluation.

Centre Leon Berard

Sarcoma

Soft Tissue Sarcoma

Surgery would be performed to resect soft tissue sarcoma with as wide margin as possible. Important vessels and nerves should be preserved.

Postoperative radiotherapy would be performed. Postoperative intensity-modulated RT (IMRT) will be performed (50 Gy in 2.0 Gy per fraction).

Anlotinib of 12mg will be administered orally, once daily, 2-days on/1-day off, until disease progression according to RECIST 1.1, death, unacceptable toxicity, or withdrawal of consent for any reasons. A cycle was considered to be 3 weeks. Anlotinib should be started 3-4 weeks after surgery, and continued for 3 months (4 cycles).

Anlotinib of 12mg will be administered orally, once daily, 2-days on/1-day off, until disease progression according to RECIST 1.1, death, unacceptable toxicity, or withdrawal of consent for any reasons. A cycle was considered to be 3 weeks. Anlotinib should be started 3-4 weeks after surgery, and continued for 3 months (4 cycles). The dose could be reduced to 8-10 mg once daily for patients who had grade 3 or 4 treatment-related toxicities, or for patients with intolerable grade 2 toxicity, despite maximum supportive care measures. If dose reduction was necessary, then the dose of anlotinib was reduced to 10 mg once daily. If further dose reduction was necessary, the dosage was reduced to 8 mg once daily. If the dosage of 8 mg once daily was not tolerable, then the patient stopped receiving anlotinib.

Anlotinib

Postoperative radiotherapy would be performed. Postoperative intensity-modu¬lated RT (IMRT) will be performed (50 Gy in 2.0 Gy per fraction). No boost dose would be added if the margin was negative, a boost dose of 10-16 Gy would be added if the margin was microscopically positive, and a boost dose of 16-18 would be added if the margin was gross positive.

Radiotherapy

Surgery

Yuhui Shen, MD

The purpose of this study is to evaluate the efficacy and safety of dose reduced postoperative radiotherapy combined with Anlotinib for patients of soft tissue sarcoma

Right now, resection and radiotherapy (RT) is the most effective and recommended treatment for soft tissue sarcoma (STS). Local recurrence rate has significantly reduced since the application of RT. However, RT has brought a lot of complications which had disturbed patients' quality of life. Anlotinib is a novel tyrosine kinase inhibitor targeting multiple factors involving tumor proliferation, vasculature, and tumor microenvironment. Anlotinib inhibits VEGF/VEGFR signaling by selectively targeting VEGFR-2,-3 and FGFR-1,-2,-3,-4 with high affinity. Anlotinib also suppresses the activity of PDGFRα/β, c-Kit, Ret, Aurora-B, c-FMS, and discoidin domain receptor 1 (DDR1), leading to significant inhibition of tumor proliferation. In phase I study, anlotinib showed promising antitumor potential against STS. In a phase II study, anlotinib showed antitumor activity in several STS with well tolerant and manageable adverse effect.

In this clinical study, investigators will explore the efficacy of Anlotinib combined with dose reduced postoperative radiotherapy on recurrence and metastasis control of STS. Patients with STS would receive standard treatment and recommended dose of radiotherapy. In addition, they will receive anotinib from 3 or 4 weeks after surgery, and continue for 3 months. The primary endpoint is Local Recurrence Free Survival (LRFS).

Anlotinib and Radiotherapy in Resectable Soft Tissue Sarcoma

A Phase II Study of Postoperative Radiotherapy With Tyrosine Kinase Inhibitor (Anlotinib) for Resectable Soft Tissue Sarcoma With High Recurrence Risk

From the time of surgery to the time of local recurrence identified by image examination.

From the time of surgery to the time of metastasis identified by image examination.

From the time of surgery to the time of death.

The occurrence of each adverse events(AEs), severe AEs(SAEs) and death according the CTCAE_5.0

Ruijin Hospital

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Adenocarcinoma

Liver Neoplasms

Liver Diseases

Antibodies

Immunoglobulins

Immunologic Factors

Treatment with Donafenib 100mg PO BID，and anti-PD-1 antibody 3mg/kg ivgtt Q2W. Treatment will last 6 months, unless the tumor recurrence.

Donafenib was taken orally twice daily, and anti-PD-1 antibody was applied biweekly.

Donafenib and anti-PD-1 antibody

Tingbo Liang, PhD

Yiwen Chen, MD

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, with more than 700,000 new cases in the world every year. China has the highest incidence and death rate of HCC in the world, accounting for 55% of the world's annual incidence and 45% of the world's annual deaths. At present, surgical resection is still one of the most effective treatments for HCC. However, the recurrence rate of tumor after hepatectomy is still very high, and the recurrence rate of 5 years is 60\~70%. Especially in patients with high-risk recurrence factors, without intervention, the cumulative recurrence rate in the first year was about 50%, about 60% in the second year, about 70% in the third year, and about 80% in the fifth year. Tumor recurrence is an important bottleneck that hinders the long-term survival of patients. Therefore, there is an urgent need for effective adjuvant therapy to reduce the postoperative recurrence rate of patients with HCC, especially high-risk patients. However, there is still a lack of standard protocols for postoperative adjuvant therapy for HCC. Here investigators intend to explore the safety and efficacy of Donafinib Combined With Anti-PD-1 Antibody as postoperative adjuvant therapy for HCC patients with high risks of recurrence.

This is a single center, open, single arm, and exploratory study. Thirty HCC patients with high risk recurrence factors after radical surgery will be enrolled. Adjuvant treatment of Donafenib combined with anti-PD-1 antibody will be given for 6 months. The primary endpoint is the cumulative percentage of patients without recurrence in the first year. The recurrence-free survival (RFS), overall survival (OS), tumor recurrence time (TTR), ECOG physical condition (ECOG PS) score, the changes of FACT-Hep based quality of life score, changes of AFP, and adverse events will be recorded and analyzed, to evaluated the efficacy and safety of this combination treatment.

Study on the Safety and Efficacy of Donafinib Combined With Anti-PD-1 Antibody as Adjuvant Therapy for HCC Patients

A Study on the Safety and Efficacy of Donafinib Combined With Anti-PD-1 Antibody as Adjuvant Therapy for HCC Patients With High Risks of Recurrence

The cumulative percentage of patients without recurrence in the first year after the primary surgery

The period from the first study treatment to disease recurrence

The period from the first study treatment to any cause of death

The changes of physical condition evaluated according to the criteria of Eastern Cooperative Oncology Group

Adverse events occurring through the study treatment, such as abnormalities or changes in laboratory examinations, physical examinations, vital signs, etc.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)	NCT02260505	Gastrointestina... Resected Gastro... Non-metastatic High Risk of Re... KIT Gene Mutati...	Imatinib mainte...	18 Years -	Centre Leon Berard
Anlotinib and Radiotherapy in Resectable Soft Tissue Sarcoma	NCT05602415	Soft Tissue Sar... High Risk of Re... Anlotinib Radiotherapy	Anlotinib Radiotherapy Surgery	18 Years -	Ruijin Hospital
Study on the Safety and Efficacy of Donafinib Combined With Anti-PD-1 Antibody as Adjuvant Therapy for HCC Patients	NCT04418401	Hepatocellular ...	Donafenib and a...	18 Years - 75 Years	Zhejiang University

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