Ensayos clínicos

Inclusion Criteria:

• Age ≥ 18 years on day of signing informed consent.
• Histologically confirmed diagnosis of:
  • Part A: advanced and/or metastatic solid tumor for which no existing options are felt to provide clinical benefit;
  • Part B: advanced and/or metastatic NSCLC in which radiological progression has been demonstrated during therapy with a PD-(L)1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit;
  • Part C: advanced and/or metastatic NEC (neuroendocrine carcinoma based on histopathology according to WHO criteria. Patients with small cell carcinoma, large cell neuroendocrine carcinoma, and neuroendocrine carcinoma not otherwise specified, of any primary organ are eligible [Nagtegaal 2020]) in which radiological progression has been demonstrated during therapy with a PD-(L)1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit.
• Measurable disease based on RECIST 1.1 (except the first 3 patients in the safety run-in).
  • NOTE: Liver lesions that have been previously embolized (bland embolization, chemo- or radio-embolization) or have undergone percutaneous thermoablation are not eligible as target lesions.
• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Life expectancy of > 3 months if not on active anti-cancer therapy.
• Willingness to provide biological samples required for the duration of the study including a fresh tumor biopsy sample.
• Adequate organ function defined as the following laboratory values obtained ≤ 14 days prior to registration:
• Hematological
  • Absolute neutrophil count (ANC) ≥ 1500/mcL;
  • Platelets ≥ 100 000/mcL;
  • Hemoglobin ≥ 9 g/dL.
• Renal
  • Serum creatinine ≤ 2.0 x ULN OR Measured or calculated creatinine clearance (CL)(per CKD-EPI) ≥ 40 mL/min for patients with creatinine levels > 2.0 x ULN.
• Hepatic
  • Direct bilirubin ≤ 1.5 x ULN;
  • Aspartate aminotransferase (AST) ≤ 2.5 x ULN;
  • Alanine aminotransferase (ALT) ≤ 2.5 x ULN Not exceeding Class A overall or B7 for HCC.
• Negative pregnancy test for female patients of childbearing potential.
• Absence of active Central Nervous System (CNS) involvement.
  • NOTE: Pre-enrollment imaging of asymptomatic patients not mandatory.
• Ability to provide written informed consent.

Exclusion Criteria: 

• Availability of and patient acceptance of curative therapy.
• Recent or ongoing serious infection, including:
  • Any active Grade 3 or higher per the National Institute of Cancer Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE, v5.0) viral, bacterial, or fungal infection within 2 weeks of registration;
  • Known seropositivity for or active infection by the human immunodeficiency virus (HIV);
  • Acute hepatitis B or acute hepatitis C (HCV). Patients with chronic hepatitis B or HCV may be enrolled provided their liver function is adequate as per inclusion criteria;
  • Known history of active TB (bacillus tuberculosis).
• Any serious health condition, which, in the opinion of the investigator, would place the patient at undue risk from the study, including uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months).
• Prior therapy within the following timeframe before the planned start of study treatment as follows:
  • Chemotherapy, small molecule inhibitors, radiation, interventional radiology (IR) procedure, and/or other investigational agent: ≤ 3 weeks or 5 half-lives, whichever is shorter;
  • Other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or experimental therapies: ≤ 4 weeks (≤ 3 weeks with documented disease progression),
• New York Heart Association (NYHA) classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or SVT).
• Any known or suspected active organ-threatening autoimmune disease, such as inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis, with the exception of hypothyroidism and type 1 diabetes that are controlled with treatment.
• Immunodeficiency or immunosuppression, including systemic corticosteroids at > 10mg/day prednisone or equivalent within 1 week prior to planned start of study treatment.
• History of severe immune-mediated adverse reaction to immune CPIs.
• Toxicities from previous therapies that have not resolved to a grade 1 or less.
• History of non-infectious pneumonitis that required steroids, or current pneumonitis.
• High volume disease, as assessed clinically via parameters such as radiologic impression and tumor markers or lactate dehydrogenase (LDH).
• Portal vein thrombosis involving more than intrahepatic portal vein branches: thrombosis of the right or left portal vein branch or the bifurcation, partial or complete obstruction of the portal vein trunk.
• Known concurrent malignancy that is progressing or requires active treatment.
  • EXCEPTIONS: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in-situ cervical cancer that has been treated with curative intent, prostate cancer confined to the prostate gland with Gleason score < 6 or PSA < 1, as well as any stage I cancer treated with curative intent or any prior cancer with a disease-free interval of ≥ 3 years.
• Other concurrent anti-cancer therapy (chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (used for a non-Food and Drug Administration (FDA) approved indication and in the context of a research investigation)).
• Has received a live vaccine within 30 days of planned start of study treatment. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; intranasal influenza vaccines (e.g., Flu-Mist® are live attenuated vaccines and are NOT allowed.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women or women of reproductive ability who are unwilling to use highly effective contraception;
  • Nursing women;
  • Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment.

Eligibility last updated 10/13/21. Questions regarding updates should be directed to the study team contact.