Pharmacokinetics and Dosimetry Studies for Optimization of Pretargeted Radioimmunotherapy in CEA-Expressing Advanced Lung Cancer Patients

Abstract

ObjectivesA phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096) was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA) to optimize bispecific antibody and labeled peptide doses, as well as the delay between their injections.MethodsThree cohorts of three patients received the anti-CEA × anti-histamine-succinyl-glycine (HSG)-humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG peptide. Patients underwent a pretherapeutic imaging session S1 (44 or 88 nmol/m2 of TF2 followed by 4.4 nmol/m2, 185 MBq, of 111In-labeled IMP288) and, 1–2 weeks later, a therapy session S2 (240 or 480 nmol/m2 of TF2 followed by 24 nmol/m2, 1.1 GBq/m2, of 177Lu-labeled IMP288). The pretargeting delay was 24 or 48 h. The dose schedule was defined based on preclinical TF2 pharmacokinetic (PK) studies, on our previous clinical data using the previous anti-CEA-pretargeting system, and on clinical results observed in the first patients injected using the same system in Netherlands.ResultsTF2 PK was represented by a two-compartment model in which the central compartment volume (Vc) was linearly dependent on the patient’s surface area. PK was remarkably similar, with a clearance of 0.33 ± 0.03 L/h/m2. 111In- and 177Lu-IMP288 PK was also well represented by a two-compartment model. IMP288 PK was faster (clearance 1.4–3.3 L/h). The Vc was proportional to body surface area, and IMP288 clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modeling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumor activity PK was variable. Organ-absorbed doses were not significantly different in the three cohorts, but the tumor dose was significantly higher with the higher molar doses of TF2 (p < 0.002). S1 imaging predicted absorbed doses calculated in S2.ConclusionThe best dosing parameters corresponded to the shorter pretargeting delay and to the highest TF2 molar doses. S1 imaging session accurately predicted PK as well as absorbed doses of S2, thus potentially allowing for patient selection and dose optimization.Trial RegistrationClinicalTrials.gov NCT01221675 (EudractCT 200800603096).

Immuno-PET Using Anticarcinoembryonic Antigen Bispecific Antibody and 68Ga-Labeled Peptide in Metastatic Medullary Thyroid Carcinoma: Clinical Optimization of the Pretargeting Parameters in a First-in-Human Trial

“…Prepretargeting radioimmunotherapy (pRIT) 111 In-IMP288 immunoscintigraphy showed good tumor targeting with a better contrast when the IMP288 dose was reduced. In our pRIT study assessing the same compounds in lung cancer patients, similar conclusions were reached with regard to the best pretargeting conditions: a pretargeting delay of 24 h, a TF2 dose of 480 nmol/m 2 , and an IMP288 dose of 24 nmol/m 2 (17). However, the constraints for therapy and imaging are different: for therapy, the injected activity must be high, which sets a minimum for the amount of injected IMP288, and the dose to the tumor must be maximum, not necessarily the tumor-to-organ ratios.…”

“…Pharmacokinetics population modeling was performed using 2-compartment models as described previously (17). …”

“…IMP288 is a bivalent histamine-succinyl-glycine hapten that can be labeled with a variety of radionuclides for therapy ( 90 Y and 177 Lu), scintigraphy ( 111 In), or PET ( 124 I, 68 Ga, and 18 F). The clinical implementation of pretargeting requires a first phase to optimize the BsMAb and peptide molar doses and the delay between the 2 injections (14)(15)(16)(17). The first clinical results were reported using TF2/ 177 Lu-IMP288 in colorectal carcinoma patients, showing fast tumor uptake and high tumor-to-background activity ratios within a few hours (14).…”

Improving theranostics in pancreatic cancer

“…A phase I clinical trial using the dock‐and‐lock technology (anti‐CEA × anti‐histamine‐succinyl‐glycine (HSG)‐humanized trivalent bispecific antibody) for pretargeting against lung cancer was performed to determine dosage of antibody and label. Interestingly, they found that a pretherapy imaging session was good indicator of absorbed doses during therapy sessions . The latest targeting moieties and chemical approaches, however, have demonstrated impressive results in animal models, establishing promise for the eventual application in the clinic.…”

“…Interestingly, they found that a pretherapy imaging session was good indicator of absorbed doses during therapy sessions. 88 The latest targeting moieties and chemical approaches, however, have demonstrated impressive results in animal models, establishing promise for the eventual application in the clinic.…”