This is a FIH study is to evaluate the safety, tolerability, PK, immunogenicity, and preliminary antitumor activity of XB010 as a single agent and in combination with pembrolizumab in subjects with locally advanced or metastatic solid tumors for whom alternative therapies do not exist or available therapies are intolerable or no longer effective.
MUMC nu alleen: single agent dose expansion cohort (dus geen pembrolizumab, alleen XB010).

MUMC doet voorlopig alleen mee met de single arm expansion cohort (dus geen pembrolizumab) enkel XB010

DRUG: XB010

IV administration of XB010

• Dose-Escalation Stage: Maximum tolerated dose (MTD) and/or Recommended dose(s) for Expansion [RDE(s)] for XB010

• Dose-Escalation Stage: Safety of XB010

• Dose-Escalation Stage: Duration of exposure of XB010 [Tolerability]

• Dose-Escalation Stage: Dose intensity of XB010 [Tolerability]

• Cohort-Expansion Stage: Preliminary antitumor activity of XB010

• Irresectable/metastatic NSCLC
• non-squamous cell or squamous cell histology) with disease progression.
• WHO 0 or 1
• Participants without an actionable mutation
  • Must have received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor, administered concurrently or sequentially for locally advanced or metastatic disease. Participants who are not eligible to receive ICI therapy are eligible if they have received platinum-containing doublet chemotherapy.
  • Did not receive more than 3 prior lines of systemic therapy in the metastatic setting (inclusive of ICI therapy given as monotherapy or in combination; rechallenge with the same agents is considered an additional line of therapy if prior disease progression on treatment has occurred).
• Participants with an actionable mutation (eg, EGFR sensitizing mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, MET Exon 14 skipping mutation, RET rearrangement, KRAS-G12C)
  • have received at least one targeted therapy for that specific genetic alteration unless such therapy is not available, or the participant is not qualified to receive such therapy.
  • Did not receive more than 3 prior lines of systemic therapy in the metastatic setting (inclusive of targeted therapy and ICI therapy given as monotherapy or in combination; rechallenge with the same agents is considered an additional line of therapy if prior disease progression on treatment has occurred

Nu in mumc enkel de single agent dose expansion cohort (dus geen pembrolizumab, alleen XB010).

1. Radiation therapy within 2 weeks before first dose of study treatment. Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.

2. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Participants with leptomeningeal disease are not eligible.

Note: Eligible participants must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.

Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed.

3. The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
   a. Acute ocular infection, acute or chronic ulcerative/cicatricial condition of conjunctiva or cornea including but not limited to ocular disorders from autoimmune diseases (eg, mucous membrane pemphigoid, Sjogren’s syndrome), severe conjunctiva/cornea scarring (eg, radiation keratopathy), severe dry eye disease, history of corneal transplantation, monocularity.

b. Peripheral neuropathy (sensory and/or motor) CTCAE Grade ≥ 2.

c. Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, torsades de pointes).

d. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic event within 6 months before first dose.

e. Thromboembolic events (eg, deep vein thrombosis or pulmonary embolism) within 3 months before first dose. Participants must have received anticoagulation therapy and be asymptomatic at the time of first dose.

Note: Incidental findings on imaging (eg, small port site thrombus) which has been adequately managed, are asymptomatic, and considered clinically insignificant may be allowed.

Note: Participants on anticoagulation therapy must be on a stable or decreasing dose for 30 days prior to enrollment.

f. History of idiopathic pulmonary fibrosis, organizing pneumonia, active drug-induced pneumonitis (prior episode allowed as long as no sequelae), or idiopathic pneumonitis.

g. Moderate to severe hepatic impairment (NCI Organ Dysfunction Working Group [ODWG]).

h. Known human immunodeficiency virus (HIV) infection unless all the following conditions are satisfied:
i. On stable anti-retroviral medications (the regimen and dosing has not required adjustment in the previous 6 months)

ii. The HIV viral load is < 400 copies/ml

iii. The CD4+ T-cell count has been maintained above 200/L in the preceding 6 months

i. History of solid organ, autologous or allogenic stem cell transplant.

j. Medically uncontrolled hypertension (blood pressure, systolic ≥ 160 mmHg and/or diastolic ≥ 100 mmHg), or requiring more than 3 antihypertensive drugs or hypertension-related complications (eg, heart failure).

4. Positive hepatitis B surface antigen (HBsAg) test or positive hepatitis C virus (HCV) antibody test.

Note: Participants with treated hepatitis C but with positive HCV antibody test followed by a negative HCV RNA test and no ongoing anti-HCV therapy are eligible.

Note: The HCV RNA test will be performed only for participants who have a positive HCV antibody test.

5. Major surgery (eg, gastrointestinal [GI] surgery, removal or biopsy of brain metastasis) within 4 weeks before first dose of study treatment. Minor surgery (eg, simple excision, tooth extraction, tumor biopsy) within 3 days before first dose. Complete wound healing from major surgery must have occurred within 3 days before first dose. Participants with clinically relevant ongoing complications from prior surgery are not eligible.

6. Corrected QT-interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 4 weeks before first dose of study treatment.
   Note: If a single ECG shows a QTcF with an absolute value > 480 ms, 2 additional ECGs at intervals of approximately 3 minutes must be performed within 30 minutes after the initial ECG, and the average of the 3 consecutive results for QTcF must be ≤ 480 ms for the participant to be eligible.

7. History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent.

8. Previously identified allergy or hypersensitivity to components of the study treatment formulations.

9. Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy.

10. Prior treatment with a MMAE ADCs

11. Investigational or live-attenuated vaccines within 28 days prior to the first dose of study treatment.