This Phase 1, open-label study will evaluate two investigational radiopharmaceuticals in adults with selected advanced or metastatic solid tumors. SKL35502 is an imaging agent used with SPECT scans to identify tumors with neurotensin receptor 1 (NTSR1), a protein found on some cancer cells, and to assess where the agent travels in the body and the radiation dose delivered to tissues. Participants with sufficient SKL35502 tumor uptake may receive SKL35501, a treatment designed to deliver targeted alpha radiation to NTSR1-expressing tumor cells.
Part A will evaluate the safety and imaging performance of SKL35502 and the safety, tolerability, pharmacokinetics, biodistribution, dosimetry, and biologically active dose range of SKL35501, as well as preliminary antitumor activity. Part B will further evaluate selected SKL35501 dose levels, including randomized low- and high-dose groups in participants with colorectal cancer, and will expand evaluation in selected tumor types. The study will also examine relationships among SKL35502 imaging, NTSR1 expression, SKL35501 tumor uptake, and treatment outcomes.
Signed ICF.
Participants should be ≥ 18 years (in the US) or ≥19 years (in South Korea) of age at the time of signing the ICF.
Histologically and/or cytologically confirmed diagnosis of selected advanced or metastatic solid tumors (relapsed/refractory disease).
Selected advanced solid tumors (PDAC, CRC, BTC, HNSCC, EC, and GC) with sufficient target (NTSR1) expression confirmed by SKL35502 imaging as defined in Inclusion Criterion 5, that have progressed following at least one prior line of therapy or for which no other standard therapy with proven clinical benefit is currently available or recommended based on the Investigator's individual risk-benefit assessment. Patients with MSI-H/dMMR CRC must have previously received and progressed on, been intolerant to, or been deemed ineligible for an FDA-approved immune checkpoint inhibitor, unless such therapy is contraindicated.
Patients with evidence of hydronephrosis.
History of solid tumor malignancy other than the diseases under study, diagnosed within (≤) the last 3 years of study enrollment, excluding adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer, in situ breast cancer, in situ prostate cancer (patients must have shown no evidence of active disease for 2 years prior to enrollment).
History of ascites or pleural effusion, unless successfully treated, asymptomatic, and not requiring treatment for > 2 months prior to C1D1.
History of myocardial infarction, unstable or severe angina, or arterial thrombotic event (such as CVA or TIA) within (≤) 12 months prior to C1D1
Sequential
SKL35501
DrugTherapeutic agent that consists of an NTSR1-targeting small molecule linked to alpha emitter 225Ac to induce killing of NTSR1-expressing tumor cells
SKL35502
Diagnostic testImaging agent that consists of an NTSR1-targeting small molecule linked to 111In to detect NTSR1-expressing tumors via SPECT imaging
Number of Participants With Treatment-Emergent Adverse Events Following SKL35502 Administration
The number of participants with at least one treatment-emergent adverse event following administration of SKL35502 will be reported. A treatment-emergent adverse event is an adverse event that begins or worsens after the first administration of SKL35502. Adverse-event severity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 6.0. Each participant will be counted once for this outcome regardless of the number of events experienced.
Absorbed Radiation Dose to Prespecified Normal Organs Following SKL35502 Administration
Absorbed radiation dose will be estimated for each prespecified normal organ following SKL35502 administration using serial imaging, organ time-activity data, and protocol-defined dosimetry methods. Organ-specific absorbed-dose values will be reported separately using the same protocol-defined absorbed-dose unit.
Absorbed Radiation Dose to Evaluable Tumor Lesions Following SKL35502 Administration
Absorbed radiation dose will be estimated for each evaluable tumor lesion following SKL35502 administration using serial imaging, lesion time-activity data, and protocol-defined dosimetry methods. Lesion-specific absorbed-dose values will be reported separately using the same protocol-defined absorbed-dose unit.
Whole-Body Radiation Dose Following SKL35502 Administration
The whole-body radiation dose following SKL35502 administration will be estimated using serial imaging and protocol-defined dosimetry methods. One whole-body radiation-dose value will be reported for each evaluable participant using the protocol-defined unit.
Number of Participants With Grade 3 or Higher Treatment-Emergent Adverse Events Following SKL35502 Administration
The number of participants with at least one Grade 3 or higher treatment-emergent adverse event following administration of SKL35502 will be reported. Severity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 6.0. Each participant will be counted once regardless of the number of events experienced.
Number of Participants With Serious Adverse Events Following SKL35502 Administration
The number of participants with at least one serious adverse event following administration of SKL35502 will be reported. Each participant will be counted once regardless of the number of serious adverse events experienced.
Number of Participants With Adverse Events of Special Interest Following SKL35502 Administration
The number of participants with at least one protocol-defined adverse event of special interest following administration of SKL35502 will be reported. Each participant will be counted once regardless of the number of adverse events of special interest experienced.
Number of Participants With Clinically Significant 12-Lead Electrocardiogram Abnormalities Following SKL35502 Administration
The number of participants with at least one clinically significant abnormality or clinically significant change from baseline in heart rate, cardiac rhythm, PR interval, QRS duration, QT interval, or QT interval corrected using Fridericia's formula will be reported. Clinical significance will be determined by the Investigator. Each participant will be counted once for this outcome.
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