Search

In sialendoscopy, ducts are dilated and the salivary glands are irrigated with saline. Contrast-enhanced ultrasound sialendoscopy (CEUSS), using microbubbles, may facilitate the monitoring of irrigation solution penetration in the ductal system and parenchyma. It is imperative to test CEUSS for its safety and feasibility in Sjögren’s syndrome (SS) patients. CEUSS was performed on 10 SS patients. The primary outcomes were safety, determined by the occurrence of (serious) adverse events ((S)AEs), and feasibility. The secondary outcomes were unstimulated and stimulated whole saliva (UWS and SWS) flow rates, xerostomia inventory (XI), clinical oral dryness score, pain, EULAR Sjögren’s syndrome patient reported index (ESSPRI), and gland topographical alterations. CEUSS was technically feasible in all patients. Neither SAEs nor systemic reactions related to the procedure were observed. The main AEs were postoperative pain (two patients) and swelling (two patients). Eight weeks after CEUSS, the median UWS and SWS flow had increased significantly from 0.10 to 0.22 mL/min (p = 0.028) and 0.41 to 0.61 mL/min (p = 0.047), respectively. Sixteen weeks after CEUSS, the mean XI was reduced from 45.2 to 34.2 (p = 0.02). We conclude that CEUSS is a safe and feasible treatment for SS patients. It has the potential to increase salivary secretion and reduce xerostomia, but this needs further investigation.

Introduction: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. Aims: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. Methods: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. Results: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07–2.37) and 1.53-fold (95%CI 1.44–1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (β=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. Conclusion: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage.Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity.Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2's dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87–68] from baseline in gBRCA carriers and 63% (CI, 72–55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy.Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400–10. ©2017 AACR.

Supplementary table 1 Observed and predicted blood toxicity profile at the start of Cycle 2 and Cycle 4 (A) and PK-toxicity model-predicted (B) neutrophil and platelet toxicity at cycle 2, day 1 and cycle 5 talozaparib 1mg/carboplatin AUC 1/5 weekly dosing: Absolute change from baseline. Supplementary Table 2: PK toxicity model estimates Supplementary Figure 1a: Goodness of fit plots of all modeled PK and PK-toxicity data. Supplementary Figure 2 Talazoparib drug clearance in gBRCA carriers versus non-carriers of talazoparib Supplementary table 3 Simulated blood toxicity profile of new dosing regimens using the PK-toxicity model. A) planned schedule B) optimized talazoparib, C) optimized carboplatin, D) optimized combination E) simulation of single agent toxicity.

Glioblastoma multiforme is the most common primary central nervous system tumor, with an incidence of 3 [...]

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C max ) and trough concentration (C trough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

Sinusoidal obstruction syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease, and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected a set of genes. To get more comprehensive insight in the genetic component, we performed an exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following a busulfan-containing conditioning regimen. Eight lead single-nucleotide polymorphisms (SNPs) were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n = 182). Three SNPs were successfully replicated, including rs17146905 ( P = .001), rs16931326 ( P = .04), and rs2289971 ( P = .03), located respectively in the UGT2B10, BHLHE22, and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in a multivariable model while controlling for nongenetic covariates and previously identified risk variants in the GSTA1 promoter. The modulation of associations by conditioning regimens was noted; KIAA1715 was dependent on the intensity of the conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed ( P = .00006) with a genotype-related SOS risk of 9.8. To our knowledge, this is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring a higher risk of SOS, which might be useful for personalized prevention and treatment strategies. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient–donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2–4 in pediatric patients, we performed an exome-wide association study in a discovery cohort (n = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group (n = 168). Significant associations were replicated for ERC1 rs1046473, PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals (p = 0.03), bone marrow stem cells recipients (p = 0.007), and serotherapy-negative patients (p = 0.004). NOP9, PLEK, and SPRED1 effects were modulated by stem cell source, and serotherapy (p < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates (p = 0.02 and p = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings.&nbsp

IntroductionWe established a promising sialendoscopic treatment for in vivo enhancement of salivation in salivary glands affected by Sjögren’s syndrome (SS). In this technique, the ducts of the salivary glands are irrigated with saline and steroids. This allows for dilatation of ductal strictures and removal of debris. Unfortunately, it is not possible to assess the delivery and penetration of saline or medications in the ductal system and parenchyma. To address this problem, we will conduct contrast-enhanced ultrasound sialendoscopy (CEUSS) using sulphur hexafluoride microbubbles. To the best of our knowledge, microbubbles have never been used for the treatment of salivary glands in SS. It is, therefore, imperative to test this application for its safety and feasibility.Methods and analysisA single-arm phase I study will be performed in 10 SS patients. Under local anaesthesia, ultrasound (US) guided infusion of the parotid and submandibular glands with microbubbles will be performed. Continuous US imaging will be used to visualise the glands, including the location of strictures and occlusions. Main outcomes will be the evaluation of safety and technical feasibility of the experimental treatment. Secondary outcomes will consist of determinations of unstimulated whole mouth saliva flow, stimulated whole mouth saliva flow, stimulated parotid saliva flow, clinical oral dryness, reported pain, xerostomia, disease activity, salivary cytokine profiles and clinical SS symptoms. Finally, salivary gland topographical alterations will be evaluated by US.Ethics and disseminationEthical approval for this study was obtained from the Medical Ethics Committee of the Amsterdam University Medical Centre, Amsterdam, The Netherlands (NL68283.029.19). data will be presented at national and international conferences and published in a peer-reviewed journal. The study will be implemented and reported in line with the Standard Protocol Items: Recommendations for Interventional Trials’ statement.Trial registration numbersThe Netherlands Trial Register: NL7731, MREC Trial Register: NL68283.029.19; Pre-results.

BackgroundThe likelihood of a tumor recurrence in patients with T3-4N0–1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28–38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019–003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence.Methods/designThis single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0–1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020.On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery on distribution and phenotype of peripheral blood immune subsets.DiscussionThe INCREASE trial will evaluate the safety and local efficacy of a combination of 4 modalities in patients with resectable, T3-4N0–1 NSCLC. Translational research will investigate the mechanisms of action and drug related adverse events.Trial registrationNetherlands Trial Registration (NTR):NL8435, Registered 03 March 2020.

Introduction This comprehensive observational study aimed to gain insight into adherence to nilotinib and the effect of (non)adherence on exposure (Cmin) and treatment outcomes. Methods Chronic myeloid leukemia (CML) patients using nilotinib were followed for 12 months. Adherence was measured by Medication Event Monitoring System (MEMS), pill count, and Medication Adherence Report Scale (MARS-5). Nilotinib Cmin and patient-reported outcomes (i.e., quality of life, side effects, beliefs, satisfaction) were measured at baseline, 3, 6, and 12 months. Results Sixty-eight patients (57.5 ± 15.0 years, 49% female) participated. Median adherence to nilotinib (MEMS and pill count) was ≥ 99% and adherence < 90% was rare. Self-reported nonadherence (MARS-5) increased in the first year of treatment to a third of patients. In line with the strong beliefs in the necessity of taking nilotinib, forgetting to take a dose was more prevalent than intentionally adjusting/skipping doses. Nilotinib Cmin were generally above the therapeutic target in 95% of patients. Patients reported a variety of side effects, of which fatigue was most frequent. The mean Cmin was higher in patients who reported severe itching and fatigue. The overall 1-year MMR rate ranged from 47 to 71%. Conclusion Substantial nonadherence (< 90%) to nilotinib was rare and nilotinib Cmin were generally above the therapeutic target. Lack of response in our group of patients was not related to nonadherence or inadequate Cmin. Nevertheless, a considerable number of patients experienced difficulties in adhering to the twice daily fasted dosing regimen, emphasizing the importance of continuous support of medication adherence in CML. Clinical trial registration NTR3992 (Netherlands Trial Register, www.trialregister.nl)

Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology. Simulations of recent trials testing 4-month regimens predicted 65% (95% confidence interval [CI], 55-74) relapse-free patients vs. 80% observed in the REMox-TB trial, and 79% (95% CI, 72-87) vs. 82% observed in the Rifaquin trial. Simulation of 6-month regimens predicted 97% (95% CI, 93-99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials.

Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we developed a quantitative system pharmacology (QSP) model to represent the anti-tumor immune response in human NSCLC that integrated our knowledge of tumor growth, antigen processing and presentation, T cell activation and distribution, antibody pharmacokinetics, and immune checkpoint dynamics. The model was calibrated with the available data and was used to identify potential biomarkers as well as patient-specific response based on the patient parameters. The model predicted that in addition to tumor mutational burden (TMB), a known biomarker for anti-PD-1 therapy in NSCLC, the number of effector T cells and regulatory T cells in the tumor and blood is a predictor of the responders. Furthermore, the model simulated a set of 12 patients with known TMB and MHC/antigen-binding affinity from a recent clinical trial (ClinicalTrials.gov number, NCT02259621) on neoadjuvant nivolumab therapy in resectable lung cancer and predicted an augmented durable response in patients with adjuvant nivolumab treatment in addition to the clinical trial protocol of neoadjuvant nivolumab treatment followed by resection. Overall, the model provides a valuable framework to model tumor immunity and response to immune checkpoint blockers to enhance biomarker discovery and performing virtual clinical trials to aid in design and interpretation of the current trials with fewer patients. Electronic supplementary material The online version of this article (10.1208/s12248-019-0350-x) contains supplementary material, which is available to authorized users.

Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing., SCOPUS: re.j, info:eu-repo/semantics/published

The low response rate of immune checkpoint blockade in breast cancer has highlighted the need for predictive biomarkers to identify responders. While a number of clinical trials are ongoing, testing all possible combinations is not feasible. In this study, a quantitative systems pharmacology model is built to integrate immune–cancer cell interactions in patients with breast cancer, including central, peripheral, tumour-draining lymph node (TDLN) and tumour compartments. The model can describe the immune suppression and evasion in both TDLN and the tumour microenvironment due to checkpoint expression, and mimic the tumour response to checkpoint blockade therapy. We investigate the relationship between the tumour response to checkpoint blockade therapy and composite tumour burden, PD-L1 expression and antigen intensity, including their individual and combined effects on the immune system, using model-based simulations. The proposed model demonstrates the potential to make predictions of tumour response of individual patients given sufficient clinical measurements, and provides a platform that can be further adapted to other types of immunotherapy and their combination with molecular-targeted therapies. The patient predictions demonstrate how this systems pharmacology model can be used to individualize immunotherapy treatments. When appropriately validated, these approaches may contribute to optimization of breast cancer treatment.

Over the past decade, several immunotherapies have been approved for the treatment of melanoma. The most prominent of these are the immune checkpoint inhibitors, which are antibodies that block the inhibitory effects on the immune system by checkpoint receptors, such as CTLA-4, PD-1 and PD-L1. Preclinically, blocking these receptors has led to increased activation and proliferation of effector cells following stimulation and antigen recognition, and subsequently, more effective elimination of cancer cells. Translation from preclinical to clinical outcomes in solid tumors has shown the existence of a wide diversity of individual patient responses, linked to several patient-specific parameters. We developed a quantitative systems pharmacology (QSP) model that looks at the mentioned checkpoint blockade therapies administered as mono-, combo- and sequential therapies, to show how different combinations of specific patient parameters defined within physiological ranges distinguish different types of virtual patient responders to these therapies for melanoma. Further validation by fitting and subsequent simulations of virtual clinical trials mimicking actual patient trials demonstrated that the model can capture a wide variety of tumor dynamics that are observed in the clinic and can predict median clinical responses. Our aim here is to present a QSP model for combination immunotherapy specific to melanoma.

Background: Veliparib, an inhibitor of Poly(ADP-ribose) polymerase (PARPi), in combination with DNA-damaging agents showed significant efficacy, especially in triple negative breast cancer (TNBC) patients. However, in I-SPY 2, approximately 42% of TNBC did not optimally respond to the veliparib based treatment. To exert therapeutic effect, drugs such as veliparib or the DNA damaging agent carboplatin must reach cancer cells at an adequate concentration. Differences within the microenvironment of the tumor (e.g. reduced vascular density and leaky endothelium) are responsible for variability in the uptake and distribution of the drug in the tumor. We hypothesize that heterogeneous or insufficient drug concentrations in the solid tumor lead to inadequate response to PARPi in some TNBC patients. First we performed a mouse xenograft study to determine the penetration and distribution of veliparib and carboplatin in TNBC tumors in mice. Methods: 1*106 MDA.MB.231, HCC70 or MDA.MB.436 cells were injected bilaterally into mamamary fat pad of a total of 36 Beige SCID mice. When the tumors exceeded 200 mm3, veliparib (20mg/kg or 60mg/kg) or placebo was orally administered 3 times daily for 3 days + Carboplatin 60mg/kg on day 1+2. These doses and dosing schedules were estimated to result equivalent plasma and tumor concentrations in mice compared to the doses currently used in clinical trials. Mice were euthanized 3 hours after the last dose of veliparib and tumors, and muscle tissues were obtained. In addition, control tissues were spiked with a broad range of concentrations of veliparib. The spatial distribution of the drugs in the tumor tissue was measured using Matrix-assisted laser desorption/ ionization mass spectrometric imaging (MALDI). The protonated molecular ion at m/z 245.1 was used to construct 2D ion maps of the tissue showing relative quantitation of drug levels. H&E staining was performed to characterize the tumors. Results: Veliparib in control tissues was detected at very low concentrations with a range of detection between 100 fmol-1nmol. After dosing, veliparib penetrates into the tumors and was detectable at both dose levels. However, drug distribution within the tumors was observed to be inhomogeneous. In spots where the drug accumulated, necrosis was observed. Veliparib accumulated in spots in the tumor and near the rim of the tumor. Differences between cell lines were observed, with the largest accumulation at the rim in BRCA mutated cells. Conclusions: Veliparib can be measured using MALDI with good specificity and sensitivity and using concentrations equivalent to patients. TNBC tumors show largely heterogeneous distribution of PARPi, with accumulation in the pushing margings of the tumor. Future analyses will determine whether this heterogeneity in drug distribution explains variability in response to PARPi therapies. Citation Format: Imke H Bartelink, Brendan Prideaux, Byron Hann, Gregor Krings, Jean-Phillippe Coppe, Lamorna Swigart-Brown, Pei Rong Evelyn Lee, Laura Esserman, Douglas Yee, Denise Wolf, Rada M Savic, Laura van t Veer. Spatial distribution of veliparib measured by matrix assisted laser desorption ionization mass spectrometry in triple negative breast cancer tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-02.

Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage. Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity. Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2's dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87–68] from baseline in gBRCA carriers and 63% (CI, 72–55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy. Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400–10. ©2017 AACR.

// Marc Ansari 1,2 , Patricia Huezo-Diaz Curtis 1,2,* , Chakradhara Rao S. Uppugunduri 1,2,* , Mohammed Aziz Rezgui 3 , Tiago Nava 1,3,5,6 , Vid Mlakar 1,2 , Laurence Lesne 1,2 , Yves Theoret 3,4,5 , Yves Chalandon 7 , Lee L. Dupuis 8 , Tao Schechter 8 , Imke H. Bartelink 9,17 , Jaap J. Boelens 9 , Robbert Bredius 10 , Jean-Hugues Dalle 11 , Saba Azarnoush 11 , Petr Sedlacek 12 , Victor Lewis 13 , Martin Champagne 14 , Christina Peters 15 , Henrique Bittencourt 3,4,5,16 and Maja Krajinovic 3 - 5,16,18 1 Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland 2 Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospital, Geneva, Switzerland 3 Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada 4 Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 5 Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Quebec, Canada 6 Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil 7 Department of Medical Specialties, Division of Hematology, Geneva University Hospital, Geneva, Switzerland 8 Department of Haematology/Oncology, Blood and Marrow Transplant Unit, The Hospital for Sick Children, Toronto, Ontario, Canada 9 Pediatric Blood and Marrow Transplantation Program, University Medical Center, Utrecht, The Netherlands 10 Department of Pediatrics, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands 11 Pediatric Hematology Department, Robert Debre Hospital, Assistance Publique, Hopitaux de Paris, Paris, France 12 Department of Pediatric Hematology and Oncology Teaching Hospital, 2nd Medical School, Charles University, Prague, Czech Republic 13 Department of Pediatrics, Alberta Children’s Hospital, Calgary, Alberta, Canada 14 Department of Hematology, Hospital Verdun, Montreal, Quebec, Canada 15 Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children’s Hospital, Vienna, Austria 16 Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 17 Department of Medicine, The University of California San Francisco, San Francisco, CA, USA 18 On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, Leiden, The Netherlands * These authors have contributed equally to this work Correspondence to: Patricia Huezo-Diaz Curtis, email: // Keywords : busulfan, pharmacokinetics, pharmacogenetics, toxicity, hematopoietic stem cell transplantion Received : July 18, 2017 Accepted : July 23, 2017 Published : August 27, 2017 Abstract Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 ( GSTA1 ) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p

Background Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. Methods MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography–mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma–mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson’s correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). Results Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26–44%), 74% (40–97%) and 46% (9–37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi–platinum interaction was observed in patients’ PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60–1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21–0.66%, P

Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.

Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a myeloid malignancy, or a lymphoid malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu + Bu at a target dose of 80-95 mg·h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg·h/L + Cy. In the latter group, Mel was added for patients with myeloid malignancy (n = 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P = not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P = .007), veno-occlusive disease (3% versus 28%; P = .003), chronic graft-versus-host disease (9% versus 26%; P = .047), adenovirus infection (3% versus 32%; P = .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P = .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P

Little information is currently available regarding the pharmacokinetics (PK) of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting busulfan PK were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age

Background Busulfan (Bu) is a DNA-alkylating agent used for myeloablative conditioning in stem cell transplantation in children and adults. While the use of intravenous rather than oral administration of Bu has reduced inter-individual variability in plasma levels, toxicity still occurs frequently after hematopoietic stem cell transplantation (HSCT). Toxicity (especially hepatotoxic effects) of intravenous (IV) Bu may be related to both Bu and/or N,N-dimethylacetamide (DMA), the solvent of Bu. In this study, we assessed the relation between the exposure of Bu and DMA with regards to the clinical outcome in children from two cohorts. Methods In a two-centre study Bu and DMA AUC (area under the curve) were correlated in pediatric stem cell recipients to the risk of developing SOS and to the clinical outcome. Result In patients receiving Bu four times per day Bu levels >1,500 µmol/L minute correlate to an increased risk of developing a SOS. In the collective cohort, summarizing data of all 53 patients of this study, neither high area under the curve (AUC) of Bu nor high AUC of DMA appears to be an independent risk factor for the development of SOS in children. Conclusion In this study neither Bu nor DMA was observed as an independent risk factor for the development of SOS. To identify subgroups (e.g., infants), in which Bu or DMA might be risk factors for the induction of SOS, larger cohorts have to be evaluated. Pediatr Blood Cancer 2014;61:306–311. © 2013 Wiley Periodicals, Inc.

Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK) adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo Uganda. In 2011 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure 26% lost weight ante-partum and median BMI post-partum was only 20.2 kg/m(2) . Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall drug exposure was reduced (LPV -33% EFV -15% ritonavir -17%) compared to well-nourished controls (P < 0.001) attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% (P < 0.001) whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure (P < 0.001) explaining 29% PK-variability. In conclusion pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority. (c) 2013 The American College of Clinical Pharmacology.

Purpose: N,N-dimethylacetamide (DMA) is administered to children during high-dose chemotherapy as a solubilizer with the intravenous formulation of busulfan (Busilvex®). DMA has shown liver toxicity in rats. However, little is known regarding its pharmacokinetics (PK) in humans. The aim of this analysis was to compare the PK of DMA after a once-daily dose of Busilvex® with the standard scheme consisting of 3-4 administrations per day in children. Methods: Out of 42 children, aged 0.1-18.9 years, receiving Busilvex®, 18 children received the first dose as a loading dose, giving a double dose of 1.4-2.0 mg/kg over a 4 h infusion followed by 15 doses of 0.7-1.0 mg/kg as 2 h infusions every 6 h. The other 24 children received Busilvex® as 3 h infusions once-daily for 4 consecutive days with a targeted busulfan AUC of 4,263 μM*min. Using NONMEM™ plasma, concentration-time data were analyzed. Assuming an increase in clearance overtime as found in our previous investigation, separate time factors for the two different dosing schedules included in the dataset were tested. Results: A one-compartment model with clearance increasing over time described the DMA kinetics sufficiently. Peak plasma concentrations of DMA, up to 3.09 mmoL/L (median 0.75 mmoL/L) for the current licensed dose regimen and up to 8.77 mmoL/L (median 3 mmoL/L) for the once-daily application, were observed. The examined increase in clearance was found to be 58 mL/h/kg and 6.1 mL/h/kg per day for the current licensed and the once-daily dose regimen, respectively. Conclusion: N,N-dimethylacetamide as solvent of lipophilic drugs such as busulfan has a linear PK in children of all ages using a dose split into one or four administrations per day. The rapid clearance with different dosing in patients of different body weights indicates that it is safe to use DMA in children in both a once and four times daily regimen.

Background and Objectives: The wide variability in pharmacokinetics of busulfan in children is one factor influencing outcomes such as toxicity and event-free survival. A meta-analysis was conducted to describe the pharmacokinetics of busulfan in patients from 0.1 to 26 years of age, elucidate patient characteristics that explain the variability in exposure between patients and optimize dosing accordingly. Patients and Methods: Data were collected from 245 consecutive patients (from 3 to 100 kg) who underwent haematopoietic stem cell transplantation (HSCT) in four participating centres. The inter-patient, inter-occasion and residual variability in the pharmacokinetics of busulfan were estimated with a population analysis using the nonlinear mixed-effects modelling software NONMEM VI. Covariates were selected on the basis of their known or theoretical relationships with busulfan pharmacokinetics and were plotted independently against the individual pharmacokinetic parameters and the weighted residuals of the model without covariates to visualize relations. Potential covariates were formally tested in the model. Results: In a two-compartment model, body weight was the most predictive covariate for clearance, volume of distribution and inter-compartmental clearance and explained 65%, 75% and 40% of the observed variability, respectively. The relationship between body weight and clearance was characterized best using an allometric equation with a scaling exponent that changed with body weight from 1.2 in neonates to 0.55 in young adults. This implies that an increase in body weight in neonates results in a larger increase in busulfan clearance than an increase in body weight in older children or adults. Clearance on the first day was 12% higher than that of subsequent days (p < 0.001). Inter-occasion variability on clearance was 15% between the 4 days. Based on the final pharmacokinetic-model, an individualized dosing nomogram was developed. Conclusions: The model-based individual dosing nomogram is expected to result in predictive busulfan exposures in patients ranging between 3 and 65 kg and thereby to a safer and more effective conditioning regimen for HSCT in children.

Purpose: Synthetic toxicity of PARP inhibitors (PARPi) and platinum salts may prohibit combination therapy in cells vulnerable to DNA damage and require alternate dosing schedule in germline BRCA (gBRCA) carriers. Experimental Design: In a phase 1 study we evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib (PARPi) and carboplatin. Pharmacokinetic-modeling explored associations between DNA vulnerability and hematologic toxicity. Differential toxicity profiles between gBRCA carriers compared to non-BRCA carriers were assessed using a PK-toxicity model accounting for dose delivery and variability in talazoparib PK. A previously developed semi-mechanistic hematologic toxicity model was used to estimate the effect of talazoparib and carboplatin on platelets and white blood cells, accounting for dose delivery of carboplatin and talazoparib and variability in talazoparib PK. To assess synergy, we compared carboplatin adduct formation alone and when used with a PARPi measured by ICP-MS in patient blood samples and fresh frozen mouse xenograft tumor sections. Results: 24 patients (8M: 16F) with solid tumors were enrolled in 4 cohorts at 0.75mg and 1mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, Q2W or Q3W). Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the maximum tolerated dose was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post-cycle 2 dose delays/reductions were required in all patients. One complete and two partial responses occurred in gBRCA patients. Four patients showed stable disease beyond four months. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 Q3W and talazoparib 1mg daily, neutrophil counts decreased by 78% (CI: 87 to 68%) from baseline in gBRCA carriers and 63% (CI: 72 to 55%) in noncarriers (p Citation Format: Mallika Sachdev Dhawan, Imke Heleen Bartelink, Rahul Aggarwal, Nela Pawlowska, Manuela Terranova-Barberio, Scott Thomas, Pamela Munster. Pharmacokinetic modeling of differential toxicity to predict alternate dosing schedules [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A090.

Background and Objectives: To prevent graft-versus-host disease and rejection in hematopoietic cell transplantation (HCT), children receive Thymoglobulin®, a polyclonal antibody acting mainly by depleting T cells. The therapeutic window is critical as over-exposure may result in delayed immune reconstitution of donor T cells. In this study, we describe the population pharmacokinetics of Thymoglobulin® as a first step towards an evidence-based dosing regimen of Thymoglobulin® in pediatric HCT. Methods: Serum active Thymoglobulin® concentrations were measured in all pediatric HCTs performed between 2004 and 2012 in two pediatric HCT centers in The Netherlands. Population pharmacokinetic analysis was performed using NONMEM® version 7.2. Results: A total of 3,113 concentration samples from 280 pediatric HCTs were analyzed, with age ranging from 3 months to 23 years old. The cumulative Thymoglobulin® dose was 10 mg/kg in 94 % of the patients given in 4 consecutive days. A model incorporating parallel linear and concentration-dependent clearance of Thymoglobulin® was identified. Body weight [for linear clearance (CL) and central volume of distribution] as well as lymphocyte count pre-Thymoglobulin® infusion (for CL) were important covariates. As such, the current dosing regimen results in higher exposure in children with a higher bodyweight and/or a lower lymphocyte count pre-Thymoglobulin® infusion. Conclusion: This model can be used to develop an individual dosing regimen for Thymoglobulin®, based on both body weight and lymphocyte counts, once the therapeutic window has been determined. This individualized regimen may contribute to a better immune reconstitution and thus outcome of allogeneic HCT.

Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. Background: Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Patients and Methods: Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Results: Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). Conclusions: When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

Background: Malnutrition may impact the pharmacokinetics (PKs) of antiretroviral medications and virologic responses in HIV-infected children. The authors therefore evaluated the PK of nevirapine (NVP), efavirenz (EFV) and lopinavir (LPV) in associations with nutritional status in a cohort of HIV-infected Ugandan children. Methods: Sparse dried blood spot samples from Ugandan children were used to estimate plasma concentrations. Historical PK data from children from 3 resource-rich countries (RRC) were utilized to develop the PK models. Results: Concentrations in 330 dried blood spot from 163 Ugandan children aged 0.7-7 years were analyzed in reference to plasma PK data (1189 samples) from 204 children from RRC aged 0.5-12 years. Among Ugandan children, 48% was malnourished (underweight, thin or stunted). Compared to RRC, Ugandan children exhibited reduced bioavailability of EFV and LPV; 11% (P = 0.045) and 18% (P = 0.008), respectively. In contrast, NVP bioavailability was 46% higher in Ugandan children (P < 0.001) with a trend toward greater bioavailability when malnourished. Children receiving LPV, EFV or NVP had comparable risk of virologic failure. Among children on NVP, low height and weight for age Z scores were associated with reduced risk of virologic failure (P = 0.034, P = 0.068, respectively). Conclusions: Ugandan children demonstrated lower EFV and LPV and higher NVP exposure compared to children in RRC, perhaps reflecting the consequence of malnutrition on bioavailability. In children receiving NVP, the relation between exposure, malnutrition and outcome turned out to be marginally significant. Further investigations are warranted using more intensive PK measurements and adequate adherence assessments, to further assess causes of virologic failure in Ugandan children.

s / Biol Blood Marrow Transplant 21 (2015) S79eS107 S102 success using HLA-matched related donors; however, use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplantrelated mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant disorders using alternative donors and PT/Cy. Design: We transplanted 9 patients with non-malignant conditions (CGD1⁄43, DKC1⁄42, DBA1⁄41, HyperIgM1⁄41, XIAP1⁄41, IPEX1⁄41) using an alemtuzamab/fludarabine based reduced intensity conditioning (RIC). All patients received GVHD prophylaxis with PT/Cy, with the addition of mycophenolate mofetil and tacrolimus for HSCT with haploidentical donors and for alkylator-sensitive diagnoses (DKC). Six patients had 10/10 HLA-matched unrelated donors, and 3 had HLA-haploidentical related donors. Results: All 9 patients successfully engrafted by day 30. Ultimately, all patients have had sustained donor engraftment sufficient to eliminate manifestations of their underlying diseases. 6 of 9 patients are full donor chimeras off immunosuppression,1 patient is a stablemixed donor chimera (76% CD3+ T cells) off immunosuppression, 1 patient is a stable mixed donor chimera on a calcineurin inhibitor (CNI), and 1 patient had secondary graft failure but was ultimately retransplanted with myeloablative conditioning using the same donor, resulting in full donor chimerism and elimination of disease. One patient developed Grade 1 and one patient Grade 2 acute GVHD, both treated successfully with steroids and a CNI. Mild skin chronic GVHD developed in 1 patient, treated successfully with phototherapy. No serious infections occurred and there was no TRM. 1 patient developed veno-occlusive disease, treated successfully with defibrotide. Disease-free survival is 89% with a median follow-up of 14 months (6-30 months). The patient with secondary graft failure is now disease-free after myeloablative transplant, for an overall disease-free survival of 100% at a median of 14 months follow-up (6-60 months). Overall survival is 100%. Conclusion: We have observed successful engraftment sufficient to eliminate manifestations of disease, limited GVHD, and no TRM in 9 patients with nonmalignant disorders using alternative donors, RIC, and PT/Cy. RIC HSCT with PT/Cy shows promise for curing nonmalignant pediatric disorders, and potentially eliminates the need for CNI use after MUD BMT. Development of prospective clinical trials to confirm these observations is warranted.

Background: There are insufficient data on pediatric antiretroviral therapy (ART) pharmacokinetics (PK), particularly for children in low- and middle-income countries. Methods: We conducted a prospective nevirapine (NVP) PK study among HIV-infected Kenyan children aged 3-13 years initiating an NVP-based ART regimen. NVP dose timing was measured through medication event monitors. Participants underwent 2 inpatient assessments: 1 at 4-8 weeks after ART initiation and 1 at 3-4 months after ART initiation. Allometric scaling of oral clearance (CL)/bioavailability (F) and volume of distribution (Vd)/F values were computed. Nonlinear mixed-effects modeling using the first-order conditional estimation with interaction method was performed with covariates. The impact of adherence on time below minimum effective concentration was assessed in the final PK model using medication event monitors data and model-estimated individual parameters. Results: Among 21 children enrolled, mean age was 5.4 years and 57% were female. CL/F was 1.67 L/h and Vd/F was 3.8 L for a median child weighing 15 kg. Participants' age had a significant impact on CL/F (P < 0.05), with an estimated decrease in CL of 6.2% for each 1-year increase in age. Total body water percentage was significantly associated with Vd/F (P < 0.001). No children had >10% of time below minimum effective concentration when the PK model assumed perfect adherence compared with 10 children when adherence data were used. Conclusions: Age and body composition were significantly associated with children's NVP PK parameters. ART adherence significantly impacted drug exposure over time, revealing subtherapeutic windows that may lead to viral resistance.

Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. This Phase 1 trial evaluates the tolerability, dose limiting toxicities (DLT) and efficacy of talazoparib in combination with carboplatin in patients with or without germ line DNA repair mutations. We hypothesize that talazoparib may overcome carboplatin resistance but induce greater toxicity in patients with DNA repair defects. Methods: Talazoparib and carboplatin pharmacokinetics (PK), safety and anti-tumor activity were evaluated in a 3+3 dose escalation design. Genetic testing, PK, pharmacodynamic effects (PD), biomarkers, and alternate dose modeling were evaluated to better understand the interaction of carboplatin and talazoparib. Results: 24 patients (median age 59y) were enrolled in 4 cohorts and treated with talazoparib 0.75 or 0.1 mg/day and carboplatin AUC 1 or 1.5 for 3/3 or 2/3 weeks. Tumor types included: breast (n = 11), prostate (n = 5), cholangiocarcinoma (n = 2), ovarian (n = 2), bladder (n = 1), adenoid cystic carcinoma (n = 1) and adenocarcinoma of unknown origin (n = 2). Germline mutations were noted in BRCA1 (n = 3), BRCA2 (n = 3), BRIP1 (n = 1), and MSH6 (n = 1) and germ line variants of uncertain significance in BRIP1 (n = 1) and BRCA2 (n = 1). Somatic mutations were found in BRCA2 (n = 1), BAP1 (n = 2) and PALB2 (n = 1). DLTs included fatigue and thrombocytopenia; other non-DLT grade 3/4 toxicities included fatigue (13%), neutropenia (33%), thrombocytopenia (33%), and anemia (58%). Post cycle 1 hematological toxicities required dose delays and reductions in almost all patients. One complete response occurred in a patient with germline BRCA1 (gBRCA1) breast cancer and a partial response (PR) in a gBRCA2 bladder cancer patient; 11 patients (pts) had stable disease (SD) for ?3 months. 5 pts had progressive disease (PD) and 6 pts are not yet evaluable. Of those with PD, 83% had prior platinum therapy, whereas in those with SD or disease response, 46% had prior platinum therapy. Effects of talazoparib/carboplatin on platelet (-11.4% vs. -1.1% P Conclusions: Mutation carriers in BRCA or other DNA repair genes responded better to this combination than non-carriers. Progression with prior platinum or PARPi did not exclude response or clinical benefit. Talazoparib and carboplatin showed significant hematologic toxicity in those with gBRCA or other germ line DNA repair mutations. Lower dosing frequencies of carboplatin when given with PARPi may be required in gBRCA mutation carriers. Citation Format: Mallika S. Dhawan, Rahul Aggarwal, Imke Bartelink, Jim Leng, Scott Thomas, Nela Pawlowska, Laurie Stevenson, Amy Jo Chien, Robin Kate Kelley, Pamela N. Munster. Carboplatin and talazoparib combination therapy results in differential efficacy and hematologic toxicity in BRCA-mutated patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT051.

2557Background: Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. This Phase 1 trial evaluates the tolerability, dose limiting toxicities (DLT) and ...