Dosing Strategies and Quantitative Clinical Pharmacology for Bispecific T-Cell Engagers Development in Oncology.

Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies.

Impact of Treatment Modality and Route of Administration on Cytokine Release Syndrome in Relapsed or Refractory Multiple Myeloma: A Meta-Analysis.

B-cell maturation antigen (BCMA)-targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM).

Case-control matching-guided exposure-efficacy relationship for avelumab in patients with urothelial carcinoma.

Exposure-response (E-R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes.

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results.

Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing.

Optimizing benefit/risk in oncology: Review of post-marketing dose optimization and reflections on the road ahead.

Oncology therapies shifted from chemotherapy to molecularly targeted agents and finally to the era of immune-oncology agents. In contrast to cytotoxic agents, molecularly targeted agents are more selective, exhibit a wider therapeutic window, and may maximally modulate tumor growth at doses lower than the maximum tolerated dose (MTD). However, first-in-patient oncology studies for molecularly targeted agents continued to evaluate escalating doses using limited number of patients per dose cohort assessing dose-limiting toxicities to identify the MTD which is commonly selected for further development adopting a 'more is better' approach that led to several post-marketing requirement (PMR) studies to evaluate alternative, typically lower, doses or dosing frequencies to optimize the benefit-risk profile.

Design and conduct considerations for studies in patients with hepatic impairment.

Despite the liver being the primary site for clearance of xenobiotics utilizing a myriad of mechanisms ranging from cytochrome P450 enzyme pathways, glucuronidation, and biliary excretion, there is a dearth of information available as to how the severity of hepatic impairment (HI) can alter drug absorption and disposition (i.e., pharmacokinetics [PK]) as well as their efficacy and safety or pharmacodynamics (PD).

Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design.

PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (cohort 1) and in patients with DDR alterations (cohort 2).

Analysis of US Food and Drug Administration Oncology Approvals on the Characterization of Hepatic Impairment Effect and Dosing Recommendations.

Patients with cancer and advanced hepatic impairment (HI) (i.e., moderate and severe impairment) are often excluded from first-in-patient, phase II, and phase III studies.

Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia.

Background: AML patients with FLT3/ITD mutations have poor response to cytarabine-based chemotherapy. FLT3 inhibitors (FLT3i) may resensitize cells to cytarabine (CYT). Improving treatment outcome of this combination may benefit from a mechanistic extrapolation approach from in vitro data.

Discordance Between Child-Pugh and National Cancer Institute Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for Oncology Compounds.

Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI).

Ribociclib Drug-Drug Interactions: Clinical Evaluations and Physiologically-Based Pharmacokinetic Modeling to Guide Drug Labeling.

Ribociclib is approved in combination with endocrine therapy as initial endocrine-based therapy for HR-positive and HER2-negative advanced breast cancer. Ribociclib is primarily metabolized by CYP3A4 and, in vitro, is an inhibitor of CYP3A and CYP1A2. Ritonavir (a strong CYP3A inhibitor) increased ribociclib 400 mg single-dose area under the plasma concentration-time curve (AUC) by 3.

Exposure-Safety Analyses of Talazoparib in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA and ABRAZO Trials.

Poly(ADP-ribose) polymerase inhibitors, such as talazoparib, may affect hematopoiesis. This analysis characterized the relationship between talazoparib exposure and the most common grade ≥ 3 hematopoietic adverse events (AEs) leading to dose modification in the phase 2 (ABRAZO) and phase 3 (EMBRACA) trials. The relationship between time-varying average talazoparib concentration (C ), along with other baseline variables, and grade ≥ 3 anemia, thrombocytopenia, and neutropenia were evaluated both by graphical examination and using univariate and multivariate Cox proportional hazard models.

Talazoparib Exposure-Efficacy Analysis in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA Trial.

In the phase 3 EMBRACA trial, treatment with the poly(ADP-ribose) polymerase inhibitor, talazoparib, led to significantly improved progression-free survival (PFS) compared with chemotherapy (hazard ratio, 0.54; 95% confidence interval, 0.41-0.

Talazoparib in Patients with a Germline BRCA-Mutated Advanced Breast Cancer: Detailed Safety Analyses from the Phase III EMBRACA Trial.

Background: In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression-free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2-mutated HER2-negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail.

Materials And Methods: Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126).

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug-Drug Interaction Studies.

Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required.

Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours.

Aims: In vitro data show that talazoparib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein transporters. This open-label, 2-arm, drug-drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P-gp inhibitor (itraconazole) and a P-gp inducer (rifampicin) on the pharmacokinetics of a single dose of talazoparib. The safety and tolerability of a single dose of talazoparib with and without itraconazole or rifampicin were also assessed.

Pazopanib Exposure Relationship with Clinical Efficacy and Safety in the Adjuvant Treatment of Advanced Renal Cell Carcinoma.

PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship between pazopanib exposure (C) and efficacy and safety was evaluated. Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C) and 250 patients at week 16 or 20 (late C).

Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations.

Ribociclib (KISQALI), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2- advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH-elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) of clinical trial data, and 4) population PK (PopPK) analysis. This multipronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH-altering agents on the absorption of ribociclib, without a dedicated drug-drug interaction trial.

Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer.

Lessons Learned: Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.

Simplification of complex physiologically based pharmacokinetic models of monoclonal antibodies.

Monoclonal antibodies (mAbs) exhibit biexponential profiles in plasma that are commonly described with a standard two-compartment model with elimination from the central compartment. These models adequately describe mAb plasma PK. However, these models ignore elimination from the peripheral compartment.

Magnetic resonance imaging-guided microdialysis cannula implantation in a spontaneous high-grade glioma murine model.

Cerebral microdialysis is used to study anticancer drug penetration in the central nervous system (CNS) and brain tumors in animal models. Genetically engineered murine models (GEMMs) have been recently used to study many aspects of CNS tumors since they represent a more relevant model than orthotopic brain tumor xenograft models. However, it is challenging to implant microdialysis cannula in these animals because T2-weighted magnetic resonance imaging (MRI) does not show the reference point (bregma) traditionally used to obtain stereotactic coordinates.

Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.

Purpose: To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420.

Experimental Design: After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b(-/-), Abcg2(-/-), Mdr1a/b(-/-)Abcg2(-/-), and Abcc4(-/-)), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration-time data, and brain penetration (P(Brain)) was estimated by the ratio of ECF-to-unbound plasma area under concentration-time curves.

Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas.

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate of the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect of modulating these transporters on topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human gliomas (U87 and MT330) and assessed topotecan tumor ECF (tECF) penetration and the effect of gefitinib on topotecan tECF penetration and intratumor topotecan distribution.

Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid.

Topotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define the role of these transporters in topotecan penetration into the ventricular cerebrospinal fluid (vCSF) and brain parenchymal extracellular fluid (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose of topotecan (4 mg/kg). vCSF penetration of unbound topotecan lactone was measured as the ratio of vCSF-to-plasma area under the concentration-time curves.