Ensayos clínicos

Inclusion Criteria:

• Patient is ≥ 18 years of age.
• 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.
• Diagnosis during dose expansion (Part 2) – All patients (with the exception of patients with MTC enroled in Groups 3, 4 and 9) must have an oncogenic RET 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 – patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treated with cabozantinib or vandetanib.
  • Group 5 – patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received SOC appropriate for their tumor type (unless there is no accepted standard therapy for the tumor type or the Investigator has determined that treatment with standard therapy is not appropriate) and must not eligible for any of the other groups.
  • Group 6 – patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation, previously treated with a selective TKI that inhibits RET, such as selpercatinib.
  • 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.
  • Group 8 – patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum-based chemotherapy (China only).
  • Group 9 – patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treated with systemic therapy (except prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease (China only).
• 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.
• Dose expansion (Part 2) patients in all groups (ecept Group 7) must have measurable disease per RECIST v1.1 (or RANO, if appropriate for tumor type).
• 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. For Part 2, Group 6, patients are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue.
• Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
• Patient provides informed consent to participate in the study.

Exclusion Criteria:

• 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. Investigators should discuss enrollment with Sponsor regarding co-mutations.
• Patient has any of the following within 14 days prior to the first dose of study drug:
  • Platelet count < 75 × 109/L;
  • Absolute neutrophil count (ANC) < 1.0 × 109/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 (Cockroft-Gault formula) or measured creatinine clearance < 40 mL/min;
  • Total serum phosphorous > 5.5 mg/dL.
• Patient has a QTcF > 470 msec. Patient has a history of prolonged QT syndrome or Torsades de pointes. Patient has a familial history of prolonged QT syndrome.
• 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).
• 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 2 weeks preceding C1D1.
• Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
• Patient received the following anticancer therapy:
  • Any systemic anticancer therapy (except for immunotherapy or other antibody therapies) and all forms of radiotherapy, within 14 days or 5 half-lives prior to the first dose of study drug. Pralsetinib may be started within these washout periods if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval;
  • Any immunotherapy or other antibody therapy within 28 days prior to the first dose of study drug (immune related toxicities must have resolved to < Grade 2 prior to starting Pralsetinib).
• Dose expansion patients in Groups 1-5 and 7 (Part 2): patient has previously received treatment with a selective RET inhibitor such as selpercatinib.
• Patient received neutrophil growth factor support within 14 days of the first dose of study drug.
• Patient requires treatment with a prohibited medication or herbal remedy that cannot be discontinued at least 2 weeks before the start of study drug administration. Pralsetinib may be started within 14 days or 5 half-lives of prior therapy if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
• 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).
• Patient has a history of another primary malignancy that has been diagnosed or required therapy (except maintenance anti-hormonal 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.
• Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
• 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.
• 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.
• If female, patient is breastfeeding.
• Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s or Sponsor'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.