A Phase 1/2 Trial of Ivonescimab With Dato-DXd or Osimertinib in Patients With Metastatic EGFR-mutant Non-small Cell Lung Cancer That Progressed on EGFR TKI Therapy
The researchers are doing this study to find out whether ivonescimab in combination with datopotamab deruxtecan- (Dato-DXd) or osimertinib are safe and effective treatments in people with non-small cell lung cancer (NSCLC) that has an EGFR mutation. The researchers will test different doses of the Dato-DXd or osimertinib with an unchanging (fixed) dose of ivonescimab to find the best dose that causes few or mild side effects in participants. Once the dose is found the researchers will test ivonescimab with Dato-DXd or osimertinib in a new group of participants to see if it is effective in treating their NSCLC with an EGFR mutation.
• Written informed consent by participant
• Biopsy-proven metastatic non-small cell lung cancer
• Somatic activating mutation in EGFR in pre-treatment tumor biopsy or cfDNA (including all mutations with sensitivity to osimertinib) by any CLIA certified assay.
• Prior treatment with 3rd-generation EGFR TKI therapy and platinum-based chemotherapy (or ineligible for platinum-based chemotherapy)
• At least one measurable (RECIST 1.1) indicator lesion not previously irradiated
• ECOG PS 0-1
• Age ≥18 years old
• Ability to swallow oral medications (Study Cohort B only)
• Adequate organ function
‣ AST, ALT ≤ 2.5 x ULN; For patients with liver metastases, AST and ALT ≤ 5 × ULN
⁃ Total bilirubin ≤ 1.5x ULN; For patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN Creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
⁃ Urine protein \< 2+ or 24 hour urine protein quantification \< 1.0 g
⁃ Absolute neutrophil count (ANC) ≥ 1500 cells/mm\^3
⁃ Hemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 2 weeks prior to screening assessment)
⁃ Platelets ≥100,000/mm3 (platelet transfusion is not allowed within 10 days prior to screening assessment)
⁃ Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 × ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy). This applies only to patients who are not on therapeutic anti-coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose.
• Female patients of childbearing age must have negative serum pregnancy test and a negative urine pregnancy test on the day of first dose prior to dosing.
• Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 90 days after the last dose of the ivonescimab and/or 3 months after last dose of Dato-DXd or 6 weeks after last dose of osimertinib
• Unsterilized male patients having sex with a female partner of childbearing potential, or a pregnant or breastfeeding partner must agree to use barrier contraception (male condom plus spermicide) for the duration of the treatment period until 90 days after the last dose of ivonescimab and/or 6 months after the last dose of Dato-DXd or 6 weeks after last dose osimertinib. Male patients with female partners of childbearing potential must have the female partner agree to use at least 1 form of highly effective contraception for the duration of the treatment period until 90 days after the last dose of ivonescimab and/or 3 months after the last dose of Dato-DXd or 6 weeks after last does of osimertinib.