177Lu-lilotomab Satetraxetan Research Articles

FDG PET/CT and Dosimetric Studies of 177Lu-Lilotomab Satetraxetan in a First-in-Human Trial for Relapsed Indolent non-Hodgkin Lymphoma—Are We Hitting the Target?

Purpose[177Lu]Lu-lilotomab satetraxetan, a novel CD37 directed radioimmunotherapy (RIT), has been investigated in a first-in-human phase 1/2a study for relapsed indolent non-Hodgkin lymphoma. In this study, new methods were assessed to calculate the mean absorbed dose to the total tumor volume, with the aim of establishing potential dose–response relationships based on 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET) parameters and clinical response. Our second aim was to study if higher total tumor burden induces reduction in the 177Lu-lilotomab satetraxetan accumulation in tumor.ProceduresFifteen patients with different pre-dosing (non-radioactive lilotomab) regimens were included and the cohort was divided into low and high non-radioactive lilotomab pre-dosing groups for some of the analyses. 177Lu-lilotomab satetraxetan was administered at dosage levels of 10, 15, or 20 MBq/kg. Mean absorbed doses to the total tumor volume (tTAD) were calculated from posttreatment single-photon emission tomography (SPECT)/computed tomography (CT) acquisitions. Total values of metabolic tumor volume (tMTV), total lesion glycolysis (tTLG) and the percent change in these parameters were calculated from FDG PET/CT performed at baseline, and at 3 and 6 months after RIT. Clinical responses were evaluated at 6 months as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).ResultsSignificant decreases in tMTV and tTLG were observed at 3 months for patients receiving tTAD ≥ 200 cGy compared to patients receiving tTAD < 200 cGy (p = .03 for both). All non-responders had tTAD < 200 cGy. Large variations in tTAD were observed in responders. Reduction in 177Lu-lilotomab satetraxetan uptake in tumor volume was not observed in patients with higher baseline tumor burden (tTMV).ConclusiontTAD of ≥ 200 cGy may prove valuable to ensure clinical response, but further studies are needed to confirm this in a larger patient population. Furthermore, this work indicates that higher baseline tumor burden (up to 585 cm3) did not induce reduction in radioimmunoconjugate accumulation in tumor.

177 Lu-Lilotomab Satetraxetan, a Novel CD37-Targeted Antibody-Radionuclide Conjugate in Relapsed Non-Hodgkin's Lymphoma (NHL): Updated Results of an Ongoing Phase I/II Study (LYMRIT 37-01)

177 Lu-Lilotomab Satetraxetan, a Novel CD37-Targeted Antibody-Radionuclide Conjugate in Relapsed Non-Hodgkin's Lymphoma (NHL): Updated Results of an Ongoing Phase I/II Study (LYMRIT 37-01)

Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

AbstractFor patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines.

The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin) is currently being evaluated in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL). Herein we have investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. Although the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines. Thus, we set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in two resistant ABC-DLBCL cell lines. We performed a viability-based screen combining 177Lu-lilotomab satetraxetan with the 384-compound Cambridge Cancer Compound Library. Drug combinations were scored using Bliss and Chou-Talalay algorithms. We identified and characterized the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as compound able to revert the resistance to RIT, alongside topoisomerase and histone deacetylases (HDAC) inhibitors.

The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37 Targeted Radioimmunotherapy in Activated B Cell like Diffuse Large B Cell Lymphoma Cell Lines

The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin®) is currently being evaluated as monotherapy in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL), as well as in a phase 1b trial in combination with rituximab for patients with relapsed/refractory FL. Herein we have investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. Although the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines: U-2932 and RIVA. Both cell lines are representative for TP53 deficient Double Expressor (DE) DLBCL. Importantly, resistance was not a consequence of reduced binding of the radioimmunoconjugate to cell surface expressed CD37. Thus, we set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in both resistant ABC-DLBCL cell lines. We performed a viability-based screen combining 177Lu-lilotomab satetraxetan with the 384-compound Cambridge Cancer Compound Library. Drug combinations were scored using Bliss and Chou-Talalay algorithms. We identified and characterized the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as compound able to revert the resistance to radioimmunotherapy (RIT), alongside topoisomerase and histone deacetylases (HDAC) inhibitors. Kinetic studies of the effect of mono- and combination therapy of U-2932 and RIVA cells with JNJ-7706621 and 177Lu-lilotomab satetraxetan are suggestive of a model in which radiation damage induced G2-arrested lymphoma cells eventually enter mitosis (repair or escape) and mitotic entry, progression and exit are impaired by JNJ-7706621 mediated inhibition of CDK1/2 and AURKA/B. Extended residence-time of cells in mitosis due to chromosome condensation and congression defects as well as spindle and mid-spindle assembly failure is likely pivotal for the increased sensitivity to persistent 177Lu-lilotomab satetraxetan deposited DNA damage, ultimately promoting cytokinesis failure (multinucleation, aneuploidy, increased cell size) and cell death. In conclusion, CD37-targeting 177Lu-lilotomab satetraxetan RIT showed activity in several ABC-DLBCL lymphoma cell lines. CD37-independent RIT-resistance was identified in two cell lines representative of aggressive DE ABC-DLBCLs with inactive TP53, and reversed by subsequent inhibition of CDK1/2 and AURKA/B by JNJ-7706621. These findings may be of potential relevance for ongoing clinical trials of 177Lu-lilotomab satetraxetan in relapsed, ASCT-non-eligible DLBCL, and may also be more generally applicable to other 177Lu-based RITs and alternative radionuclide utilizing targeted therapies. Future pre-clinical investigations are required to elucidate the potential application of CDK1/2 and AURKA/B inhibitors as a strategy to revert RIT resistance in TP53 deficient cancers. Disclosures Rødland: Nordic Nanovector ASA: Patents &amp; Royalties, Research Funding. Melhus:Nordic Nanovector ASA: Employment, Equity Ownership, Patents &amp; Royalties. Generalov:Nordic Nanovector ASA: Employment, Equity Ownership, Patents &amp; Royalties. Bertoni:Nordic Nanovector ASA: Research Funding; Oncology Therapeutic Development: Research Funding; PIQUR Therapeutics AG: Other: travel grant, Research Funding; HTG: Other: Expert Statements ; Amgen: Other: travel grants; Astra Zeneca: Other: travel grants; Jazz Pharmaceuticals: Other: travel grants; NEOMED Therapeutics 1: Research Funding; Acerta: Research Funding; ADC Therapeutics: Research Funding; Bayer AG: Research Funding; Cellestia: Research Funding; CTI Life Sciences: Research Funding; EMD Serono: Research Funding; Helsinn: Consultancy, Research Funding; ImmunoGen: Research Funding; Menarini Ricerche: Consultancy, Research Funding. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership, Patents &amp; Royalties. Syljuåsen:Nordic Nanovector ASA: Patents &amp; Royalties, Research Funding. Patzke:Nordic Nanovector ASA: Employment, Patents &amp; Royalties.

Cell Cycle Kinase Inhibitors Potentiate the Effect of 177lu-Lilotomab Satetraxetan in Treatment of Aggressive Diffuse Large B-Cell Lymphoma Cell Lines

BackgroundCD37 is an internalizing transmembrane glycoprotein widely expressed on mature B-cells and B-cell malignancies. The next generation anti-CD37 radioimmunoconjugate (RIC) 177Lu-lilotomab satetraxetan (Betalutin®), containing the beta-emitting radionuclide lutetium-177, is currently being tested as one-time injection therapy in a clinical phase 2b trial for follicular lymphoma (FL) and phase 1 trial for diffuse large B-cell lymphoma (DLBCL).We recently reported the systems biology analysis of germinal center like (GCB) and activated B-cell like (ABC) DLBCL cell lines to CD37 targeting radioimmunotherapy (RIT) (Melhus, et al., PF642 at EHA23, Stockholm, 2018). 177Lu-Lilotomab satetraxetan showed generally promising activity against DLBCL cell lines, but treatment resistance was evident in a subset of cell lines. Resistance was not attributable to differences in CD37 expression nor correlated to genetic hallmarks of aggressiveness such as aberrations in TP53, BCL2 and MYC. In the present study we aimed at identifying resistance reversing drug combinations with 177Lu-lilotomab satetraxetan in two RIT resistant aggressive ABC-DLBCL cell lines.Materials and methodsU-2932 and RIVA cells were treated for 18 hours with 177Lu-lilotomab satetraxetan (600 MBq/mg; 1 or 0.5 µg/ml), washed, and seeded on micro-well plates pre-printed with a drug library of 384 approved anti-cancer compounds at 10, 100, and 1000 nM (screen). For validation experiments, cells were treated with three different doses of 177Lu-lilotomab satetraxetan as described above and seeded on pre-printed plates with gradients of candidate hits ranging from 1-1280 nM. Cell viability was monitored at days 3 to 6 post seeding using a cell viability assay (RealTime-Glo™). Drug combinations were scored using Bliss and Chou-Talalay theorems.ResultsCompounds scoring in both cell lines included inhibitors targeting cell cycle kinases that regulate transition through mitosis, such as CDK1/2, AURKA/B, PLK1, as well as enzymes with important roles in DNA integrity surveillance and repair, such as topoisomerases. If the compounds also have or are being tested in clinical trials for treatment of non-Hodgkin lymphoma (NHL) they were considered candidates for further studies. PLK1 inhibitors BI2536 and GSK461364 potently inhibited cell proliferation at < 20 nM, with additional, but not synergistical benefit of combination with 177Lu-Lilotomab satetraxetan. The AURKA/B inhibitor Alisertib synergistically inhibited cell proliferation in combination treatment, but showed adverse effect at concentrations >160 nM, possibly owing to inhibition of a secondary target. The pan-CDK inhibitor JNJ-7706621 showed little effect alone but strongly synergized with 177Lu-lilotomab satetraxetan in inhibition of proliferation at doses > 80 nM. U-2932 and RIVA cells arrested in G2-phase with elevated DNA damage (flow cytometry; P-γ-H2AX and DNA staining) 18 hrs after treatment with 177Lu-lilotomab satetraxetan. Resistance reversal by anti-mitotics may thus underlie concomitant radiation during inhibitor mediated M-phase arrest of cells that eventually evaded G2-phase arrest.ConclusionIn summary, combinatorial drug screening identified cell cycle kinase inhibitors as promising partners for combination treatment of aggressive DLBCL with 177Lu-lilotomab satetraxetan, warranting further exploration in pre-clinical models. [Display omitted] DisclosuresRødland:Nordic Nanovector ASA: Patents & Royalties, Research Funding. Melhus:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Syljuåsen:Nordic Nanovector ASA: Patents & Royalties, Research Funding. Patzke:Nordic Nanovector ASA: Employment, Patents & Royalties.

LYMRIT 37-01: A Phase I/II Study of 177lu-Lilotomab Satetraxetan (Betalutin®) Antibody-Radionuclide-Conjugate (ARC) for the Treatment of Relapsed Non-Hodgkin's Lymphoma (NHL) — Analysis with 6-Month Follow-up

LYMRIT 37-01: A Phase I/II Study of 177lu-Lilotomab Satetraxetan (Betalutin®) Antibody-Radionuclide-Conjugate (ARC) for the Treatment of Relapsed Non-Hodgkin's Lymphoma (NHL) — Analysis with 6-Month Follow-up

Administration of Beta-Emitting Anti-CD37 Radioimmunoconjugate Lutetium (177Lu) Lilotomab Satetraxetan as Weekly Multiple Injections Increases Maximum Tolerated Activity in Nude Mice with Non- Hodgkin Lymphoma Xenografts

Lutetium (177Lu) lilotomab satetraxetan (177Lu-lilotomab) is a novel anti-CD37 radioimmunoconjugate (RIC) currently in Phase 2b clinical trial for treatment of non-Hodgkin lymphoma (NHL). The aim of the current study was to investigate tolerability and anti-tumor efficacy of multiple dosing of 177Lu-lilotomab in vivo. Nude mice with subcutaneous (s.c.) NHL (Ramos) xenografts were given 2, 3 or 4 weekly injections of 300 MBq/kg 177Lu-lilotomab or NaCl. Treatment tolerability was assessed by body weight, hematology and histopathological evaluation. A separate experiment in mice without xenografts was performed to collect long term toxicity data. Mice in this study were dosed more conservatively with the intention that all mice should survive until end of experiment and were administered 2 or 4 weekly injections of 200 MBq/kg 177Lu-lilotomab or NaCl. Total accumulated activity of 900 MBq/kg 177Lu-lilotomab given as three weekly injections was tolerated by nude mice with s.c. Ramos xenografts, which is 50 % higher than the maximum tolerated activity (MTA) of a single injection of 530-600 MBq/kg. In the long-term toxicity animals, the highest accumulated activity tested, 800 MBq/kg, was also well tolerated. Radioactivity-dependent transient reduction in white blood cell and platelet counts occurred in all treated groups, with nadir 1-3 weeks after last injection. This toxicity was radioactivity dependent and consistent with histopathological changes in hemolymphopoietic tissues. Significant tumor growth delay measured as time to reach 4 times intial tumor volume was observed in all groups given multiple injections of 300 MBq/kg 177Lu-lilotomab compared to NaCl control group (p&lt;0.001). In conclusion, weekly injections of 177Lu-lilotomab increase the accumulated MTA from 530 to 900 MBq/kg in nude mice, allowing the total injected activity and hence the radiation dose to tumor to be increased without increasing the toxicity to normal tissues.

OA170] Myelosuppression in non–hodgkin lymphoma patients treated with 177Lu-lilotomab satetraxetan can be predicted by a model with red marrow absorbed dose as the only parameter

Purpose 177Lu-lilotomab satetraxetan is an antibody-radionuclide conjugate therapy for non–Hodgkin lymphoma, which is currently in a phase 1/2-study. The primary toxicity is transient myelosuppression. The aim of this work was to determine if a linear model including red marrow absorbed dose and various clinical factors can be used to predict myelosuppression. Methods Patient characteristics and dosimetric data for 17 patients were included. All patients had no or minor bone marrow infiltration. The percentage reduction of neutrophils and platelets at nadir compared to baseline was used as to indicate myelosuppression. Platelets and neutrophils were analysed separately. The Common Terminology Criteria version 4.0 were used to grade thrombocytopenia and neutropenia. A total of six factors believed to affect bone marrow reserve were tested: Red marrow absorbed dose, age at treatment, baseline cell-counts, history of prior external beam radiation therapy, total number of previous chemotherapy treatments (including rituximab) and elapsed time since the last chemotherapy treatment. Predictors were found using ordinary least square fitting, testing all possible subsets of variables. A significance level of 0.05 was used. A leave 1-out analysis was used to validate the final model. Results The typical patient, as described by the mean and standard deviation, was 69 (+/−10) years of age at treatment, had previously been treated 2.8 (+/−1.8) times with chemotherapy and might have previously received external beam radiation therapy (5/17 patients). Elapsed time since the last chemotherapy was 20.9 (+/−17.2) months. Mean red marrow absorbed dose was 1.45 (+/−0.45) Gy. Of the sub-sets of predictors investigated, only a model consisting solely of the red marrow absorbed dose was significant (p = 0.048 for platelets and 0.027 for neutrophils). Model coefficients indicate total loss of both platelets and neutrophils at 3 Gy. The leave-1 out analysis resulted in correct prediction of CTCAE-grading +/−1 grade for 76.5 % (13/17) and 88.2 % (15/17) of the patients for thrombocytopenia and neutropenia, respectively. Conclusions A linear model with red marrow absorbed dose as the only parameter predicted myelosuppression in 177Lu-lilotomab satetraxetan treated patients.

Pre-dosing with lilotomab prior to therapy with 177Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients

Purpose177Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses.MethodsTwo of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m2 BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq 177Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student’s t tests were used for all statistical analyses.ResultsOrgans with distinct uptake of 177Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1–4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p = 0.04) and arm 4 (p = 0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p < 0.01).Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1–4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p = 0.05 and p = 0.02). No statistically significant difference between arms 1 and 4 was found.ConclusionsRM is the primary dose-limiting organ for 177Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m2 was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab.

Red Marrow-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with 177Lu-Lilotomab Satetraxetan, a Novel Anti-CD37 Antibody-Radionuclide Conjugate.

Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin lymphoma were included for RM dosimetry. Hybrid SPECT and CT images were used to estimate the activity concentration in the RM of L2-L4. Pharmacokinetic parameters were calculated after measurement of the 177Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The mean absorbed doses to RM were 0.9 mGy/MBq for arm 1 (lilotomab+) and 1.5 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arms 1 and 2 (Student t test, P = 0.02). Total RM-absorbed doses ranged from 67 to 127 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve was higher with lilotomab predosing than without (P = 0.001), whereas the volume of distribution and the clearance of 177Lu-lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging-based, method underestimated the RM dose and did not show any correlation with toxicity. Predosing with lilotomab reduces the RM-absorbed dose for 177Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematologic toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images.