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1.
Cancer Res ; 83(2): 301-315, 2023 01 18.
Article in English | MEDLINE | ID: mdl-36351060

ABSTRACT

Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype. SIGNIFICANCE: The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.


Subject(s)
Membrane Proteins , Prostatic Neoplasms , Animals , Humans , Male , Mice , Antibodies, Monoclonal , Immunotherapy , Intracellular Signaling Peptides and Proteins/immunology , Intracellular Signaling Peptides and Proteins/metabolism , Ligands , Membrane Proteins/immunology , Membrane Proteins/metabolism , Positron-Emission Tomography , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/therapy , Prostatic Neoplasms/pathology , Zirconium , Neuroendocrine Tumors/diagnostic imaging , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/therapy
2.
Clin Cancer Res ; 27(10): 2773-2781, 2021 05 15.
Article in English | MEDLINE | ID: mdl-33441294

ABSTRACT

PURPOSE: Investigate the safety and efficacy of LY3415244, a TIM-3/PD-L1 bispecific antibody that blocks TIM-3 and PD-L1 in patients with advanced solid tumors. PATIENTS AND METHODS: A phase I, multicenter, open-label study was conducted in patients with advanced solid tumors. Patients were dosed every 2 weeks intravenously with flat doses of LY3415244 escalating from 3 to 70 mg. The primary endpoints were safety, tolerability, and identification of the recommended phase II dose. RESULTS: Between November 2018 and October 2019, 12 patients were enrolled into four cohorts and received at least one dose of LY3415244. Two patients (16.7%) developed clinically significant anaphylactic infusion-related reactions and all patients developed treatment-emergent antidrug antibodies (TE-ADA). ADA titers were sometimes very high and negatively impacted soluble TIM-3 target engagement in most patients. ADA epitope specificity was against both TIM-3 and PD-L1 arms of the bispecific antibody; most TE-ADAs initially targeted the TIM-3 arm after the first dose. Preexisting ADAs against LY3415244 were also detected in normal (unexposed) human serum samples. One patient with PD-1 refractory non-small cell lung cancer had a near partial response (-29.6%). CONCLUSIONS: This TIM-3 and PD-L1 bispecific format was associated with unexpected immunogenicity targeting both arms of the bispecific antibody, resulting in early study termination. Epitope specificity analysis revealed an initial response toward the TIM-3 arm and presence of preexisting ADAs to the bispecific molecule in the general population. This experience emphasizes the importance of thorough analyses for preexisting ADAs as part of immunogenicity risk assessment of novel antibodies.See related commentary by de Spéville and Moreno, p. 2669.


Subject(s)
Antibodies, Bispecific/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Bispecific/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Biomarkers , Disease Management , Drug Administration Schedule , Drug Monitoring , Female , Humans , Male , Middle Aged , Molecular Targeted Therapy/methods , Neoplasms/diagnosis , Neoplasms/etiology , Neoplasms/mortality , Treatment Outcome
3.
Clin Pharmacol Ther ; 106(1): 195-203, 2019 07.
Article in English | MEDLINE | ID: mdl-30636281

ABSTRACT

Generic substitution of antiepileptic drugs is generally not advised by neurologists. The present study investigated the switchability of gabapentin 800 mg tablets (Neurontin and Gabasandoz) using an individual bioequivalence (IBE) study design with two batches of each product and assessed whether between-batch and between-formulation variability in exposure play a significant role in the within-subject variability. The trial was analyzed according to the US Food and Drug Administration (FDA) framework to establish IBE. The IBE was shown between both products with the 95% upper confidence bound of the IBE criterion being -2.01 and -2.31 for area under the concentration-time curve from zero to infinity (AUC0-inf ) and peak plasma concentration (Cmax ), respectively. Subject-by-formulation variability (1.35%) was negligible compared with the within-subject variability of AUC0-inf with Neurontin (19.0%) and Gabasandoz (23.6%). Inclusion of an additional batch did not significantly change this within-subject variability (20.2% and 23.6%, respectively). This study shows that substitution of gabapentin 800 mg tablets of Neurontin and Gabasandoz should be possible without affecting clinical outcomes.


Subject(s)
Anticonvulsants/pharmacokinetics , Drugs, Generic/pharmacokinetics , Gabapentin/pharmacokinetics , Adult , Anticonvulsants/blood , Area Under Curve , Cross-Over Studies , Drug Substitution , Drugs, Generic/analysis , Female , Gabapentin/blood , Healthy Worker Effect , Humans , Male , Middle Aged , Therapeutic Equivalency , United States , United States Food and Drug Administration/standards , Young Adult
4.
Orphanet J Rare Dis ; 12(1): 163, 2017 10 16.
Article in English | MEDLINE | ID: mdl-29037240

ABSTRACT

BACKGROUND: Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(-related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored. RESULTS: KH176 was well tolerated up to and including a single dose of 800 mg and multiple doses of 400 mg b.i.d. for 7 Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000 mg and at a multiple dose of 400 mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000 mg and multiple doses of 400 mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000 ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed. CONCLUSION: The study deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d. and has a pharmacokinetic profile supportive for a twice daily dosing. Only at high doses, KH176 causes clinically relevant changes in cardiac electrophysiology, including prolonged QTc interval and changes in T wave morphology. A Phase 2 clinical trial (100 mg b.i.d., orally) has been conducted recently of which the final results are expected Q1 2018. TRIAL REGISTRATION: NCT02544217 . Registered. ISRCTN43372293 . Retrospectively registered.


Subject(s)
Mitochondrial Diseases/drug therapy , Mitochondrial Diseases/genetics , Rare Diseases/drug therapy , Rare Diseases/genetics , Adolescent , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Humans , Male , Middle Aged , Young Adult
5.
Acta Clin Belg ; 72(1): 24-28, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28151378

ABSTRACT

Both urothelial (UC) and renal cell cancer (RCC) are highly immunogenic tumours. Recent advances in cellular immunity understanding have resulted in a successful new class of therapeutic agents. Interaction between the programmed cell death 1 (PD1) on regulatory T-cells (Treg) and programmed cell death 1 ligand (PDL1) on cancer cells inhibits an effective immune response and is an important mechanism for cancer cells to evade the immune system. Monoclonal anti-PD1 and anti-PDL1 antibodies inhibit this interaction and are called checkpoint inhibitors. As in non-small lung cancer and melanoma, these agents have shown to be highly active agents in UC and RCC. In metastatic or inoperable UC, no good second line therapy exists and checkpoint inhibitors have shown to be active. Multiple Randomized Clinical Trials (RCT) are underway both in second line and adjuvant settings which could change daily practice. In RCC, an anti-PD1 antibody, Nivolumab, has already proven to be effective in prolonging overall survival, and is included in current guidelines in metastatic RCC in second and third line. RCTs with other anti-PD1 and anti-PDL1 antibodies are ongoing both in metastatic and adjuvant setting. Checkpoint inhibitors have breathed new life into immunotherapy in urologic cancers and are rapidly being included in practice guidelines.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Immunity, Cellular/drug effects , Urologic Neoplasms/drug therapy , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Renal Cell/immunology , Humans , Nivolumab , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Urologic Neoplasms/immunology
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