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

Abstract

Objectives: A 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.

Methods: Three 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/m(2) of TF2 followed by 4.4 nmol/m(2), 185 MBq, of (111)In-labeled IMP288) and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m(2) of TF2 followed by 24 nmol/m(2), 1.1 GBq/m(2), of (177)Lu-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.

Results: TF2 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/m(2). (111)In- and (177)Lu-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.

Conclusion: The 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 registration: ClinicalTrials.gov NCT01221675 (EudractCT 200800603096).

Keywords: SPECT; SPECT/CT; dosimetry; lung cancer; pharmacokinetics; pretargeting; radioimmunotherapy; scintigraphy.

Figures

Figure 1

Pharmacokinetics of the bispecific antibody TF2. Each patient received two infusions of TF2 at 7 or 8 days intervals (except patient 5). Blood samples were collected at selected time intervals during and after each infusion and centrifuges. TF2 concentrations were measured using a specific ELISA. The pharmacokinetics was then modeled using a two-compartment model and a population approach. Data collected after both infusions were fitted using a single set of parameters. Results (open squares) are plotted as a semilog plot with the population (dashed lines) and individual (solid lines) fitted curves.

Figure 2

Pharmacokinetics of the labeled hapten IMP288. Each patient received TF2 infusions then 24 or 48 h after each infusion, they received an infusion of IMP288 labeled with indium-111 after the first TF2 infusion or labeled with lutetium-177 after the second. Blood samples were collected at selected time intervals during and after each infusion, centrifuged, and counted. Indium-111 counts were corrected to match lutetium-177 radioactive half-life, and the figure shows IMP288 activity concentrations. The pharmacokinetics was modeled using a two-compartment model and a population approach. Results (open squares) are plotted as a semilog plot with the population (dashed lines) and individual (solid lines) fitted curves.

Figure 2

Pharmacokinetics of the labeled hapten IMP288. Each patient received TF2 infusions then 24 or 48 h after each infusion, they received an infusion of IMP288 labeled with indium-111 after the first TF2 infusion or labeled with lutetium-177 after the second. Blood samples were collected at selected time intervals during and after each infusion, centrifuged, and counted. Indium-111 counts were corrected to match lutetium-177 radioactive half-life, and the figure shows IMP288 activity concentrations. The pharmacokinetics was modeled using a two-compartment model and a population approach. Results (open squares) are plotted as a semilog plot with the population (dashed lines) and individual (solid lines) fitted curves.

Figure 3

Whole body and SPECT/CT images of patient 1 (cohort I). Whole body and SPECT/CT images were acquired 24 and 48 h after injection of 111In-labeled IMP288 (A,C) and 177Lu-labeled IMP288 (B,D). Patient 1 included in the first cohort had SCLC and a CEA level of 79 ng/mL. These images showed low tumor targeting in liver, mediastinum, and lung metastases.

Figure 4

Whole body and SPECT/CT images of patient 4 (cohort II). Whole body images (anterior view) were acquired 4, 24, 48, and 72 h after injection of 111In-labelled IMP288 (A) and 177Lu-labelled IMP288 (B). Patient 4, included in the cohort II, had NSCL and a CEA level of 275 ng/mL. These images clearly shows lung tumor targeting in whole body and SPECT/CT images [(C) with 111In-labelled IMP288 and (D) with 177Lu-labelled IMP288]. According to RECIST criteria, the disease was considered as stable at 4 weeks, but progressive at 3 months. Patient 4 was the only patient with HAHA against TF2 > 50 ng/mL detected 1 month after the last TF2 injection.

Figure 5

Normalized organ-absorbed doses per cohort assessed in the pretherapeutic (A) and therapeutic sessions (B). No significant statistical differences were found between groups. Abbreviations: WB, RL, LL, RK, LK, and RM stand, respectively, for whole body, right lung, left lung, right kidney, left kidney, and red marrow.

Figure 6

Tumor normalized-absorbed doses per cohort assessed in the pretherapeutic (A) and therapeutic sessions (B). Cohort I was significantly (p < 0.002) different from cohorts II and III.