Ensayos clínicos

Inclusion Criteria:

• Signed informed consent form (ICF) and ability to comply with protocol requirements.
• Known tumor TP53 mutation status from recent or archival sample.
• Histologically and/or cytologically confirmed solid tumor malignancy:
  • Safety lead-in portion:
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced non-central nervous system (CNS) primary tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment, and for whom pembrolizumab, or pembrolizumab-based therapy, is considered appropriate in the opinion of the investigator. Primary CNS tumors are excluded. Patients with clinically stable, known metastatic tumors to the CNS are eligible. CNS radiography is not required in the absence of suspicion for clinical involvement.
  • Phase 2 Expansion portion:
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced gastric or gastroesophageal junction (GEJ) tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment. Patients with clinically stable, known metastatic tumors to the CNS are eligible with Medical Monitor approval. CNS radiography is not required in the absence of suspicion for clinical involvement. Prior treatment with anti-PD1/anti-PD-L1 therapy is prohibited;
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced bladder/urothelial tumors that have progressed after first line treatment, or who are intolerant to first line treatment, or who are unable to receive first line treatment with cisplatin-based chemotherapy. Patients with clinically stable, known metastatic tumors to the CNS are eligible with Medical Monitor approval. CNS radiography is not required in the absence of suspicion for clinical involvement. Prior treatment with anti-PD-1/anti-PD-L1 therapy is prohibited;
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy. Patients with clinically stable, known metastatic tumors to the CNS are eligible with Medical Monitor approval. CNS radiography is not required in the absence of suspicion for clinical involvement.
• Adequate organ function as defined by the following laboratory values:
  • Creatinine clearance > 30 mL/min (by Cockcroft-Gault method;
  • Total serum bilirubin < 1.5 × upper limit of normal (ULN) unless due to Gilbert’s syndrome, tumor involvement, hemolysis or considered an effect of regular blood transfusions;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN, unless due to involvement by the underlying malignancy.
• Age ≥ 18 years at the time of signing the ICF.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Projected life expectancy of ≥ 12 weeks.
• In the expansion portion, measurable disease meeting the following criteria:
  • At least 1 lesion of ≥ 10 mm in the longest diameter (LD) for a non-lymph node or ≥ 15 mm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1;
  • Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show subsequent evidence of substantial size increase (ex., 20% increase in LD) to be deemed a target lesion.
• Negative serum or urine pregnancy test prior to study treatment initiation in female subjects of childbearing potential.
• Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter.

Exclusion Criteria:

• Known history of untreated human immunodeficiency virus (HIV)/HIV with a detectable viral load or active hepatitis B or active hepatitis C infection.
• Any of the following cardiac abnormalities:
  • Myocardial infarction within six months prior to registration;
  • New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction (LVEF) < 40%;
  • A history of familial long QT syndrome;
  • Symptomatic atrial or ventricular arrhythmias not controlled by medications;
  • QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the Medical Monitor.
• Concomitant malignancies or previous malignancies with less than a 1-year disease-free interval at the time of signing consent. Subjects with adequately treated basal or squamous cell carcinoma of the skin, or adequately treated carcinoma in situ (e.g, cervix) may enroll irrespective of the time of diagnosis. Patients with controlled, advanced prostate cancer are permitted.
• Pregnancy or lactation.
• Active uncontrolled systemic infection.
• An autoimmune condition requiring ≥ 10 mg (or equivalent corticosteroid) prednisone daily, or any other systemic immunosuppressive treatment within 28 days of first dose of study therapy.
• Known history of active tuberculosis.
• Current (non-infectious) pneumonitis, or a history of pneumonitis that required steroids.
• A live vaccine administered within 30 days of the first dose of study treatment.
• Receipt of any investigational product within 14 days or 5 half-lives prior to study treatment initiation, whichever is shortest.
• Prior intolerance to pembrolizumab or other anti-PD-1/PD-L1 agents.