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A Global Multicenter Randomized Placebo-Controlled Phase 3 Trial To Compare The Efficacy And Safety Of Fruquintinib Plus Best Supportive Care To Placebo Plus Best Supportive Care In Patients With Refractory Metastatic Colorectal Cancer - FRESCO-2

Studio Clinico

Patologia: Tumori del colon retto

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: 

Fase di studio: III

Linee di trattamento: Seconda linea, Terza/N linea

Criteri di inclusione: 

- Provide written informed consent;
- Age ≥18 years;
- Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented, according to country level guidelines;
- Subjects must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib.
- Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy;
Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the subject's country unless the patient is ineligible for treatment with a checkpoint inhibitor;
- Subjects who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Subjects who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible;
- Body weight ≥40kg;
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
- Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions;
- Expected survival >12 weeks.
- For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the subject. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with spermicide). The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
- Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the subject's home country unless the patient is ineligible for treatment with a BRAF inhibitor.

Criteri di esclusione: 

- Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed;
- Serum total bilirubin >1.5 × the upper limit of normal (ULN). Patients with Gilbert syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in patients without hepatic metastases; ALT or - AST >5 × ULN in patients with hepatic metastases;
- Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockroft-Gault equation.
- Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Subjects with greater than 2+ proteinuria by dipstick must undergo a 24-hour urine collection to assess urine protein level;
- Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg despite optimal medical management;
- International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended to receive anticoagulants for prophylactic purposes;
- History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator's judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening;
- History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening;
- History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
- Stroke and/or transient ischemic attack within 12 months prior to screening;
Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) <50% by echocardiogram;
- Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.
- Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes.
- Systemic anti-neoplastic therapies (except for those described in Exclusion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
- Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
- Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
- Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug;
- Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 60 days prior to the first dose of study drug or unhealed surgical incision;
- Any unresolved toxicities from a previous antitumor treatment greater than CTCAE v5.0 Grade 1 (except for alopecia or neurotoxicity grade≤2);
- Known human immunodeficiency virus (HIV) infection;
- Known history of active viral hepatitis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
- Clinically uncontrolled active infection requiring IV antibiotics;
Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or inferior vena cava;
- Women who are pregnant or lactating;
- Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment are excluded;
- Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;
- Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
- Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at undue risk of harm based on the investigator's assessment;
- Known hypersensitivity to fruquintinib (or placebo) or any of its inactive ingredients including the azo dyes Tartrazine - FD&C - Yellow 5 and Sunset yellow FCF - FD&C Yellow 6;
- Subjects who have received prior fruquintinib;
- Live vaccine <28days before the first dose of study drug(s). Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

Trattamento sperimentale: 

fruquintinib plus best supportive care

Trattamento di controllo: 

placebo plus best supportive care

Obiettivi primari dello studio: 

Overall Survival [ Time Frame: up to 10 years ]
    To evaluate the overall survival of fruquintinib plus BSC compared to placebo plus BSC in subjects with refractory mCRC.

Centri partecipanti

Nord Italia

Fondazione Poliambulanza Istituto Ospedaliero
Via Bissolati 57 - 25124 Brescia - BS

 

IRCCS A.O.U. San Martino - IST
Largo Rosanna Benzi 10 - 16132 Genova - GE
U.O. Oncologia Medica 1

Riferimento: Dr.ssa Carla Curti
Telefono: 0105554386
Email: carla.curti@hsanmartino.it

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI
NB: Arruolamento pazienti non ancora attivo

Riferimento: Dr.ssa Maria Di Bartolomeo
Telefono: 0223903066
Email: maria.dibartolomeo@istitutotumori.mi.it

 

Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI
NB: Arruolamento pazienti non ancora attivo

 

Ospedale Niguarda Ca' Granda
Piazza dell'Ospedale Maggiore 3 - 20162 Milano - MI

 

Istituto Clinico Humanitas Rozzano
Via Manzoni 56 - 20089 Rozzano - MI

Riferimento: Prof. Armando Santoro
Telefono: 0282246280

 

Istituto Oncologico Veneto IRCCS
Via Gattamelata 64 - 35128 Padova - PD

Riferimento: Dr.ssa Sara Lonardi
Email: sara.lonardi@iov.veneto.it

 

AUSL/IRCCS di Reggio Emilia
Viale Risorgimento 80 - 42123 Reggio nell'Emilia - RE

Riferimento: Dr.ssa Maria Banzi
Telefono: 0522296756
Email: maria.banzi@ausl.re.it

 

Ospedale San Bortolo, Vicenza
Viale Rodolfi 37 - 36100 Vicenza - VI

 

Centro Italia

Ospedale Riuniti Umberto I - Lancisi-Salesi
Via Conca 71 - 60020 Ancona - AN
NB: Arruolamento pazienti non ancora attivo

Riferimento: Prof.ssa Rossana Berardi
Telefono: 0715964169
Email: Rossana.Berardi@ospedaliriuniti.marche.it

 

AOU Pisana - Santa Chiara
Via Roma 67 - 56126 Pisa - PI

Riferimento: Dr.ssa Chiara Cremolini
Telefono: 050992192
Email: chiaracremolini@gmail.com

 

Sud Italia e isole

Ospedale 'Card. G. Panico'
Via San Pio X 4 - 73039 Tricase - LE

Riferimento: Dr. Emiliano Tamburini
Telefono: 0833773111
Email: sperimentazionicliniche@piafondazionepanico.it

 

Istituto Nazionale Tumori IRCCS Fondazione Pascale
Via Mariano Semmola - 80131 Napoli - NA

Riferimento: Dr. Antonio Avallone
Telefono: 0815903360
Email: a.avallone@istitutotumori.na.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2020-000158-88

Data di inserimento: 14.09.2021

Promotore

Hutchison Medipharma Limited

CRO

Syneos Health Italy S.r.l.

Principal Investigator ITALIA

IRCCS Ospedale Policlinico San Martino, Genova

Riferimento: Prof. Alberto Sobrero

Telefono: 0105554386

Email: alberto.sobrero@hsanmartino.it

Localita: Genova

 

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