Randomized Controlled Trial comparing two groups of Patients with High-Risk, Localized Soft Tissue Sarcoma of the Extremity: the first one receiving Neoadjuvant Pembrolizumab with Radiotherapy and Adjuvant Pembrolizumab after surgery, and the second one receiving Radiotherapy and surgery, aiming to assess the safety and efficacy profile of Pembrolizumab

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori, Sarcoma Alliance for Research through Collaboration

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Musculoskeletal Diseases [C05], Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

11 Dec 2019 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-517858-10-00

EudraCT number

2018-001360-39

ClinicalTrials.gov

NCT03092323

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To investigate whether neoadjuvant radiotherapy combined with pembrolizumab followed by surgical resection and adjuvant pembrolizumab improves disease-free survival for patients with high-risk soft tissue sarcoma of the extremity (undifferentiated pleomorphic sarcoma or de-differentiated/pleomorphic liposarcoma, tumor size > 5 cm, grade 2 or 3 out of 3) compared to radiotherapy alone followed by surgical resection

Secondary objectives 1

1. 1. Valutare la sopravvivenza libera da ricaduta loco-regionale, sopravvivenza libera da malattia metastatica, e sopravvivenza in generale in entrambe le coorti di studio. 2. Verificare la sicurezza di pembrolizumab neoadiuvante somministrato con radioterapia frazionata convenzionale su sarcoma dei tessuti molli degli arti.

Conditions and MedDRA coding

high-risk soft tissue sarcoma of the extremity (undifferentiated pleomorphic sarcoma or dedifferentiated/pleomorphic liposarcoma, tumor size > 5 cm, grade 2 or 3 out of 3)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1 Age equal to or higher than 12 years 2 Histologically confirmed diagnosis of grade 2 or 3 out of 3 UPS or dedifferentiated/pleomorphic LPS of the extremity (including limb girdle, i.e. shoulder or hip) that measures greater than 5 cm in any direction as assessed by imaging; Alternative terms for UPS meeting inclusion criteria include but are not limited to the following • pleomorphic undifferentiated sarcoma • unclassified spindle cell sarcoma • spindle cell sarcoma not otherwise specified • pleomorphic spindle cell sarcoma • pleomorphic fibroblastic sarcoma • undifferentiated high-grade pleomorphic sarcoma • pleomorphic sarcoma with prominent inflammation • pleomorphic sarcoma with giant cells • malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory subtypes) • fibrosarcoma • myxofibrosarcoma (if located deep to the fascia in muscle).3 Patients with non-melanomatous skin cancer, in situ carcinoma, or low-risk prostate cancer can be enrolled.4 ECOG Performance Status of 0 or 1. 5 Resectable primary tumor with no evidence of metastatic disease by imaging. Imaging must be performed within 45 days of Day 1 of study.6 Adequate organ function within 10 days of Day 1 of study defined as: 6.1 Absolute Neutrophil Count (ANC) = 1,500/mcL 6.2 Platelets = 100,000/mcL 6.3 Hemoglobin = 9 g/dL or =5.6 mmol/L without transfusion or erythropoietin dependency (within 7 days of assessment) 6.4 Serum creatinine < 1.5 X institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance or GFR > 60 mL/min for subject with creatinine level > 1.5 X ULN; Note: Creatinine clearance should be calculated per institutional standard. 6.5 ALT (SGOT) and AST (SGPT) = 2.5 X institutional ULN 6.6 Serum bilirubin = 1.5 X institutional ULN OR direct bilirubin < ULN for subjects with total bilirubin levels > 1.5 X ULN 6.7 Albumin > 2.5 mg/dL. 7 Written, voluntary informed consent. 8 Fertile men and women of childbearing potential must agree to use an effective method of birth control from Day 1 of study and for 120 days after last pembrolizumab administration in both sexes. Women of childbearing potential include pre-menopausal women and women within the first 2 years of the onset of menopause. Women of childbearing potential must have a negative pregnancy test = 72 hours prior to Day 1 of study.

Exclusion criteria 1

1. 1 Precedente chemioterapia, terapia target a piccole molecole, o terapia radiante per l'attuale diagnosi di sarcoma 2 Precedente terapia radiante in eccesso di 20 Gy in sede attuale di malattia. Non è ammessa sovrapposizione con precedenti campi di irradiazionein eccesso di 20 Gy. 3 Malattie maligne attive concomitanti, clinicamente significative, entro due anni dall'arruolamento in studio. 4 Pazienti con sarcoma recidivo locale dopo chirurgia sola solo eleggibili all'arruolamento a condizione che siano soddisfatti gli altri criteri di inclusione. 5 Pazienti con malattia grave e /o incontrollata concomitante che secondo l'investigatore può mettere a rischio la sicurezza o compromettere la compliance con il protocollo 6 Chirurgia maggiore entro 4 settimane dal Giorno 1 dello studio o da cui il paziente non si è adeguatamente ripreso. 7 Assunzione concomitante di una terapia da studio o di un agente sperimentale entro 4 settimane al momento dell'arruolamento. 8 Donne gravide o che stanno allattando oppure che stanno cercando una gravidanza o uomini che stanno cercando una paternità nella durata prevista dello studio clinico, che inizia con la visita di pre-screening o screening e si conclude a 120 giorni dopo l'ultima dose di pembrolizumab. 9 Impossibilità ad attenersi alle procedure richieste dal protocollo. 10 Diagnosi di immunodeficienza o terapia sistemica con steroidi in atto o qualsiasi altra forma di terapia immunosoppressiva per via orale o endovenosa entro 7 giorni prima della prima dose di trattamento da studio. 11 Storia nota di TBC attiva (Bacillus Tuberculosis) 12 Ipersensibilità al pembrolizumab o a qualsiasi dei suoi eccipienti 13 Malattia metastatica o coinvolgimento dei linfonodi regionali. Una TAC del torace sarà obbligatoria prima dell'arruolamento per valutare la presenza di malattia metastatica. Nodulo/i polmonare/i < 5 mm senza diagnosi istologica non può/possono essere motivo di esclusione a causa dell'aspecificità della TAC torace. In presenza di noduli di dimensioni maggiori (6 – 10 mm), ma che appaiono stabili rispetto a immagini precedenti risalenti a 6 mesi prima o che una PET 18FDG segnala come non metastatici, l'arruolamento è consentito. Noduli polmonari >10 mm vanno considerati metastatici se non diversamente comprovato da biopsia/resezione o aspetto stabile per almeno 6 mesi nell'imaging.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Disease-free survival will be the primary efficacy endpoint. Disease recurrence is defined as clinically diagnosed or biopsy-confirmed recurrent sarcoma at a site distant to the primary tumor, including nodal metastasis, loco-regional recurrence, and death without documented recurrence.

Secondary endpoints 1

1. 1. To evaluate the loco-regional recurrence-free survival (RFS), the distant disease free survival, and overall survival (OS) in both patient cohorts. 2. To test the safety of neoadjuvant pembrolizumab administered with conventionally fractionated radiotherapy targeting soft tissue sarcoma of the extremity

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Clinical Trial Center

Public contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Clinical Trial Center

Sarcoma Alliance for Research through Collaboration

Sponsor organisation

Sarcoma Alliance for Research through Collaboration

Address

Frank Lloyd Wright Drive, Lobby A, Suite 3100 24

City

Ann Arbor MI

Postcode

49105

Country

United States

Sponsor responsibilities

Article 77 compliance

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact point sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications