This is an open label, single-arm, multicentre dose escalation (Part 1) and dose expansion (Part 2) study to evaluate different combinations of 3 radioactive dose levels of 177Lu-TLX250 administered intravenously with 3 different doses of peposertib in patients with CAIX-expressing solid tumors.
Histologically confirmed advanced or metastatic solid tumor that has progressed on or during/after recognized standard of care therapies and are not eligible for resection, or patients that are not eligible or not consenting to recognized standard of care therapies.
At least one measurable lesion on CT/MRI according to RECIST 1.1 with corresponding 89Zr-TLX250 uptake (i.e., CAIX positive).
CAIX positivity in at least 75% of the total lesion volume (defined as 89Zr- TLX250 uptake with intensity significantly greater than normal liver [i.e., standardized uptake value [SUV]max at least 1.5 times SUV of normal liver]).
ECOG status 0 or 1.
Prior 177Lu-TLX250 or other radioligand therapy; or any prior CAIX targeting therapy.
Known hypersensitivity to compounds of similar chemical or biologic composition to peposertib, girentuximab radiolabelled by zirconium or lutetium, any excipient in the study medication or any other intravenously administered human proteins/peptides/antibodies.
Administration of any radionuclide within 10 half-lives of the radionuclide prior to signature of the ICF.
Patients who have had chemotherapy, definitive radiation, biological cancer therapy, or investigational agent/device within 28 days of first planned dose of study therapy.
Sequential
89Zr-TLX250
Diagnostic testSingle IV administration followed by 89Zr-DFO-girentuximab PET/CT (or PET/MRI) scan at screening and approximately 8-10 weeks (±1 week) after Cycle 3 Day 1, as well as at the end of treatment visit (if feasible). The PET/CT should be obtained within 4-7 days after 89Zr-TLX250 administration
177Lu-TLX250 and Peposertib
Combination productDose escalation and de-escalation for the determination of the Maximum tolerated combination/ Recommended phase 2 dose. All subjects will receive 177Lu-TLX250 intravenously on day 1 and Peposertib BID on days 4-21 of each 84-day cycle.
Safety parameter Dose Limited Toxicity (DLT)
Dose level toxicity evaluation using Partial Ordering Bayesian Logistic Regression Model Method (PO-BLRM)
Safety parameter Laboratory Examinations
Frequency of occurrence and severity of abnormal findings in safety investigations regarding Laboratory examinations
Safety parameter Vital signs
Frequency of occurrence and severity of abnormal findings in safety investigations regarding the vital signs
Safety parameter ECG
Frequency of occurrence and severity of abnormal findings in the 12-lead ECG (ECG QT interval)
Overall Survival (OS)
Overall Survival (OS), determined from enrollment , until death from any cause
Tumor objective response rate (ORR)
Tumor response in terms of objective response rate (ORR) (solid tumor tissue response and overall radiological response \[tumor response by RECIST 1.1 and overall radiological response by RECIST 1.1\])
Progression-free survival (PFS)
Progression free survival (PFS) defined as the time from enrollment to disease progression confirmed by radiology, clinical progression or death (whichever comes first)
Immunogenicity by formation of ADA(HACA) in blood
This outcome will be measured by analyzing the incidence of ADA(HACA) formation in blood on day 1, day 22, Day 43, Day 57 of each cycle (each cycle is 84 days) and at the end of treatment visit.
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Telix Pharmaceuticals (Innovations) Pty Limited
Lead sponsor
Merck KGaA, Darmstadt, Germany
Collaborator
