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Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases.

ABSTRACT: The objective of the present study was to validate the use of intralesional injection of interleukin-2 (IL-2) in patients with skin and soft-tissue melanoma metastases. A total of 24 patients with AJCC stage III or IV melanoma and single or multiple skin and soft-tissue metastases were included. Interleukin-2 injections were administered intralesionally into the total number of cutaneous and soft-tissue metastases accessible from the skin, 2-3 times weekly, over 1-57 weeks. Single doses varied from 0.6 to 6 x 10(6) IU, depending on lesion size. The clinical response was monitored by sonography and confirmed by histopathology; response evaluation was confined to the intralesionally treated tumours. Complete response (CR) of the treated metastases was achieved in 15 patients (62.5%), the longest remission lasting 38 months to date. In five patients, partial response (PR) was achieved (21%) and in another three patients, progressive disease was observed (one patient not assessable). A total of 245 metastases were treated with CR in 209 (85%), and PR in 21 (6%). The therapy was generally well tolerated; the observed adverse events were mainly of grade 1-2 severity. Immunohistochemical studies showed the tumour cells undergoing apoptosis and revealed a mixed character of the inflammatory infiltrate. The unusual high CR rate in metastatic melanoma of 62.5% and the limited toxicity suggest that treatment of skin and soft-tissue melanoma metastases with intralesional injection of IL-2 may be a safe and effective alternative to conventional therapies. The optimal dosage and duration of this therapy still remain to be defined in larger prospective multicentre trials.

SUBMITTER: Radny P

PROVIDER: S-EPMC2394422 | biostudies-other | 2003 Nov

REPOSITORIES: biostudies-other

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Project description:INTRODUCTION:Up 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 ANALYSIS:STEREOSARC 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 REGISTRATION:The trial is registered on ClinicalTrials.gov (ID: NCT03548428). ETHICS AND DISSEMINATION:This 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.

Project description:IntroductionAlthough the introduction of multimodal treatment of soft tissue sarcoma improved local tumour control, local failure still occurs in a good number of patients. Therefore, further improvement of current treatment strategies is necessary. The proposed study treatment will combine standard external beam radiation and the orally administered receptor tyrosine kinase inhibitor sunitinib.Methods and analysisPatients with soft tissue sarcoma will receive sunitinib and irradiation as neoadjuvant treatment. Radiotherapy will be administered as intensity modulated radiation therapy with a total dose of 50.4 Gy in 28 fractions (5 1/2 weeks). Patients will receive sunitinib daily for 2 weeks prior to and then concurrently with irradiation. Sunitinib will be given in two dose levels. The first dose level will be 25 mg sunitinib per os daily. The second dose level will be 37.5 mg. A dose modification schedule according to a 3+3 design will be applied. Restaging and tumour resection will be performed 6 weeks after completion of sunitinib and irradiation. Primary outcome measures will be the dose-limiting toxicity and maximal tolerated dose of sunitinib administered concurrently with irradiation. Toxicity of the study treatment will be documented according to Common Terminology Criteria of Adverse Events (CTCAE) 4.0. Secondary outcome measures will be the response to the study treatment and morbidity of the tumour resection. Imaging response will be determined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria comparing MRI performed prior to and 6 weeks after completion of study treatment. Pathological response will be determined evaluating the fraction of non-viable tumour in the resection specimen. Resection morbidity will be evaluated according to CTCAE 4.0.Ethics and disseminationApproval was obtained from the ethics committee II of the University of Heidelberg, Germany (Reference number 2011-064F-MA). Furthermore, the study was approved by the German Federal Institute for Drugs and Medical Devices (Reference number 4037708).Trial registration eudract2007-002864-87 Clinicaltrials.gov: NCT01498835.

Project description:PurposePembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial ( ClinicalTrials.gov identifier: NCT02085070).Patients and methodsWe enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1.ResultsSix patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not.ConclusionPembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti-programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases.

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Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases.

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