Safety and efficacy of letetresgene autoleucel alone or with pembrolizumab for relapsed/refractory multiple myeloma.

This pilot study assessed the safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794), a genetically modified autologous T-cell therapy targeting New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1 isoform A (LAGE-1a)-positive myeloma cells, alone or in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma. Eligible patients expressed NY-ESO-1 and/or LAGE-1a and either HLA-A∗02:01, ∗02:05, or ∗02:06. Patients received lete-cel single infusion alone (arm 1) or with pembrolizumab (arm 2). 127 patients were screened, and 6 patients (3 per arm) were enrolled; patients in arm 1 and 2 received lete-cel alone, or with pembrolizumab, respectively. All patients exhibited grade 3/4 cytopenias, which resolved or improved to grade 1. One patient (arm 1) had grade 3/4 lete-cel-related adverse events (AEs); 2 patients (arm 2) had grade 3/4 AEs related to lete-cel and lymphodepletion. Three patients with grade 1/2 cytokine release syndrome (CRS) exhibited elevated post-lete-cel interleukin-6 levels versus those without CRS. Pooled overall response rate was 50% including 1 patient each with confirmed clinical response, very good clinical response, and partial response, and progression-free survival ranged from 1.3 to 5.2 months. Responders (arm 1: n = 1; arm 2: n = 2) had a time-to-response of 3 weeks, duration of response of 2.1 months. Two responders, but no nonresponders, exhibited elevated cytokine levels after lete-cel infusion. Lete-cel had a manageable safety profile and demonstrated clear but transient antitumor activity in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT03168438.

Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma.

Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.

Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment.

PURPOSE: The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI). METHODS: Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5-3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (Cmax), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure-response (E-R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens. RESULTS: In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E-R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients. CONCLUSION: These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI. TRIAL REGISTRATION: NCT03359850; registered December 2, 2017.

Thorough QTc Evaluation and the Safety of Supratherapeutic Doses of Odanacatib in Healthy Subjects.

Assessing risk for QTc interval prolongation in a thorough QTc study is a standard recommendation when evaluating new chemical entities. As part of the clinical development program for odanacatib, an oral selective inhibitor of cathepsin K previously in development for the treatment of osteoporosis, 2 clinical studies in healthy subjects assessed pharmacokinetics and overall safety (including potential for delayed ventricular repolarization) of a supratherapeutic dose. In study 1, subjects received a supratherapeutic dose regimen of odanacatib (300 mg on day 1, then daily multiple doses of 25 mg to day 21) or placebo. In study 2 (days 1-4), subjects received the odanacatib supratherapeutic dose regimen or moxifloxacin (positive control, single 400-mg dose on day 4; matching placebo for odanacatib/moxifloxacin) or placebo. All doses were administered with a high-fat meal. In study 1 (N = 12), the supratherapeutic dosing regimen achieved exposure ∼3.5-fold of the proposed therapeutic dose (50 mg once weekly) and was sufficiently well tolerated to permit assessment in the thorough QTc study (study 2). In study 2 (N = 116), the primary objective was placebo-corrected change from baseline in QTcF interval (Fridericia's correction), assessed by replicate electrocardiograms (12-lead Holter recordings; days -1 through 7). Supratherapeutic odanacatib dosing was not associated with increased risk of prolonged QT interval, unlike moxifloxacin (confirming assay sensitivity). Pooled safety data across both studies suggested that the safety profile of odanacatib at high exposures was similar to placebo, with a small clustering of oral cavity adverse events. Odanacatib was not associated with increased risk of prolonged QT interval.

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis.

Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 µM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.

Individuals with CYP2C8 and CYP2C9 reduced metabolism haplotypes self-adjusted ibuprofen dose in the Coriell Personalized Medicine Collaborative.

OBJECTIVES: The objectives of this study were to determine whether differences in CYP2C8 and CYP2C9 haplotype influence the dose of ibuprofen self-administered by individuals, and to examine the potential relationship between CYP2C8 and CYP2C9 reduced metabolism haplotypes and adverse events. PARTICIPANTS AND METHODS: We investigated relationships between genetic variations in CYP2C8 and CYP2C9 and ibuprofen use, dose, and side effects (reported by questionnaire) in 445 participants from the Coriell Personalized Medicine Collaborative. RESULTS: Carriers of reduced metabolism haplotypes for CYP2C8 (*2, *3, *4) and CYP2C9 (*2, *3) were significantly (P=0.0171) more likely than those lacking these variants to take less than the recommended dose of ibuprofen, after controlling for sex, age, race, and cohort. In contrast to ibuprofen dose, there were no differences in ibuprofen use frequency or reported side effects based on haplotype. However, there are often no early signs of acute kidney injury, the most serious side effect of elevated ibuprofen exposure. CONCLUSION: These results suggest a subset of individuals with genetic variation in CYP2C8 and CYP2C9 recognize that they obtain adequate drug efficacy with lower ibuprofen doses, or take lower doses due to prior side effects. However, most (82.6%) individuals with reduced metabolism haplotypes nonetheless took recommended or higher doses, potentially putting them at increased risk for side effects.

Theoretic criteria for antibody penetration into solid tumors and micrometastases.

UNLABELLED: Targeting tumors with antibody-based therapeutics is a complex task presenting multiple kinetic barriers. Antibody internalization and clearance inhibit uptake both in solid tumors, limited by tumor vascular permeability, and in micrometastases, limited by diffusion. METHODS: A modeling exercise is used to introduce 2 simple criteria that must be less than unity for saturation of both tumors and micrometastases. The clearance modulus and the Thiele modulus are ratios of the plasma clearance rate and antibody catabolism, respectively, to the tumor tissue penetration rate. RESULTS: Even low rates of antigen internalization from constitutive membrane turnover can significantly retard antibody penetration. Rapid clearance of single-chain variable fragments also hinders uptake, often more than counterbalancing their more rapid extravasation and diffusion. CONCLUSION: The model illustrates that with the large resistance from the tumor capillary, antibodies may be more suitable for targeting micrometastases than vascularized tumors.