Interventionnelle

Étude de phase 1 portant sur le BLU-667, un inhibiteur RET hautement sélectif, chez des patients atteints de
cancer  de  la  thyroïde,  de  cancer  bronchique  non  à petites cellules (CBNPC) et d’autres tumeurs solides avancées avec altération de RET

Code de l’étude

Promoteur

Blueprint Medicines Corporation

Tumeur éligible

RET-altered Non Small Cell Lung Cancer, RET altered Medullary Thyroid Cancer, RET-altered Papillary Thyroid Cancer, RET-altered Colon Cancer, RET-altered Solid Tumors

Type d’étude

Interventionnelle

Phase

Nombre de patients à inclure

360 participants

Contact

    studydirector@blueprintmedicines.com

Centres

Internationale, France: Institut Gustave Roussy, Institut Bergonié (bordeaux), CHRU Lille, Centre Leon Berard (Lyon), Institut Claudius Regaud (Toulouse)

Objectifs

Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BLU-667 [ Time Frame: Cycle 1 (28 days) of treatment for MTD and at the end of every cycle (28 days) for RP2D for approximately 12 months or earlier if patient terminates from the study ]

Number of patients with adverse events and serious adverse events [ Time Frame: Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 30 days after the last dose ]

Overall response rate [ Time Frame: Approximately every 8 weeks during treatment, 14 days after the last dose, and every 3 months after the last dose (up to 2 years) in patients without progressive disease

Critères d’inclusion

•    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 medullary thyroid cancer (MTC), or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.
•    Diagnosis during dose expansion (Part 2) - All patients (with the exception of Groups 3 and 4) must have an oncogenic RET-rearrangement/fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central 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 fusion previously treated with a platinum-based chemotherapy.
•    Group 2 - patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy.
•    Group 3 - patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib.
•    Group 4 - patient must have pathologically documented, definitely diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treat with cabozantinib and/or vandetanib.
•    Group 5 -patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups.
•    Group 6 - patients must have a pathologically documented, definitely diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective TKI that inhibits RET
•    Group 7 - patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups
•    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 the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.
•    Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.

Critères d’exclusion

•    Patient's cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1 or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation.
•    Patient has any of the following within 14 days prior to the first dose of study drug:
   •    Platelet count < 75 × 10^9/L.
   •    Absolute neutrophil count <1.0 × 10^9/L.
   •    Hemoglobin < 9.0 g/dL (red blood cell transfusion and erythropoietin 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.
   •    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.
   •   Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert's disease.
Estimated (Cockcroft-Gault formula) or measured creatinine clearance <40 mL/min.
   •    Total serum phosphorus > 5.5 mg/dL
   •    QT interval corrected using Fridericia's formula (QTcF) >470 msec or history of prolonged QT syndrome or Torsades de pointes, or familial history of prolonged QT syndrome.
   •    Clinically significant, uncontrolled, cardiovascular disease.
   •    Central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms.
   •    Clinically symptomatic interstitial lung disease or interstitial pneumonitis including radiation pneumonitis
   •    Patients in Groups 1-5 and 7 (Part 2) previously treated with a selective RET inhibitor