Patologia: Neoplasie del polmone, Altre neoplasie
Fase di studio: I,
Richiesta mandatoria di tessuto: Sì
Linee di trattamento: Seconda linea, Terza/N linea
Criteri di inclusione:
1. Patient is ≥ 18 years of age.
2. Diagnosis during dose escalation (Part 1) – Pathologically documented, definitively diagnosed non-resectable advanced solid tumor.
• All patients treated at doses > 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.
• Part 1 enrichment patients must have MTC or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.
3. Diagnosis during dose expansion (Part 2) – All patients in Groups 1, 2 and 4 must have a RET-altered (excluding synonymous and nonsense mutations) solid tumor, as determined by local testing of tumor or circulating tumor nucleic acid in blood; as detailed below.
• Group 1 – patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET rearrangement that was previously treated with a TKI that inhibits RET, such as cabozantinib, vandetanib, ponatinib, sorafenib and alectinib.
• Group 2 – patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET rearrangement that was not previously treated with a TKI that inhibits RET.
• Group 3 – patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit.
• Group 4 - patients must have a pathologically documented, definitively diagnosed advanced solid tumor with a RET alteration, other than NSCLC and MTC.
4. Patient must have non-resectable disease that has progressed following standard therapy or has not adequately responded to standard therapy, or the patient must be intolerant to or have declined available standard therapies, or there must be no
accepted standard therapy for their disease.
5. Dose expansion (Part 2) patients must have measurable disease per RECIST.
6. Patient agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator.
7. Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2.
8. Patient or legal guardian provides informed consent to participate in the study.
Criteri di esclusione:
1. Patient has NSCLC with a targetable mutation in EGFR, ALK, or ROS1.
2. Patient has any of the following within 14 days prior to the first dose of study drug:
a. Platelet count < 75 × 109/L.
b. Absolute neutrophil count (ANC) < 1.0 × 109/L.
c. Hemoglobin < 9.0 g/dL (red blood cell [RBC] transfusion and erythropoietin (EPO) may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug.
d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if hepatic metastases are present.
e. Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert’s disease.
f. Estimated (Cockroft-Gault formula) or measured creatinine clearance < 40 mL/min.
3. Patient has a QT interval corrected using Fridericia’s formula (QTcF) > 470 msec. Patient has a history of prolonged QT syndrome or Torsades de pointes. Patient has a familial history of prolonged QT syndrome.
4. Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous
6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g., Type II second degree heart block or third degree heart block).
5. Patient has central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the two weeks preceding C1D1.
6. Patient received any anti-cancer therapy (including both systemic therapy and radiotherapy) within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug.
7. Dose expansion patients (Part 2): Patient has previously received treatment with a selective RET inhibitor, such as LOXO-292, unless the patient’s tumor has acquired a resistant mutation known to be sensitive to BLU-667.
8. Patient received neutrophil growth factor support within 14 days of the first dose of study drug.
9. Patient requires treatment with a prohibited medication or herbal remedy cancer, that cannot be discontinued at least 2 weeks before the start of study drug administration.
10. Patient has had a major surgical procedure within 14 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
11. Patient has a history of another primary malignancy that has been diagnosed or required therapy within the past year. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, curatively treated localized thyroid cancer, and completely resected carcinoma in situ of any site.
12. Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
13. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 30 days after the last dose of study drug.
Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 90 days after the last dose of study drug.
14. Pregnant females, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the first dose of study drug. Females with β-hCG values that are within the range for
pregnancy but are not pregnant (false-positives) may be enrolled with written consent of the Sponsor, after pregnancy has been ruled out. Females of non-childbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral
oophorectomy; hysterectomy) do not require a serum β-hCG test.
15. If female, patient is breastfeeding.
16. Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
Trattamento di controllo:
Obiettivi primari dello studio:
• To determine the MTD and RP2D of BLU-667.
• To determine the safety and tolerability of BLU-667
Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI
Riferimento: Dr. Giuseppe Curigliano
Ospedale Niguarda Ca' Granda
Piazza dell'Ospedale Maggiore 3 - 20162 Milano - MI
Riferimento: Dr. Salvatore Siena
Numero di iscrizione a registro: 2016-004390-41
Data di inserimento: 18.04.2018
Istituto Europeo di Oncologia - Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative
Riferimento: Dr. Giuseppe Curigliano