Search

DPYD-guided dosing has improved the safety of fluoropyrimidine-based chemotherapy in recent years. However, severe toxicity remains in ~ 23% of patients not carrying DPYD variant alleles treated with capecitabine. Therefore, we developed a predictive model based on patient-related and treatment-related factors aimed at estimating the risk of developing severe capecitabine-related toxicity. The nomogram was developed using data from two large clinical trials (NCT00838370 and NCT02324452). Patients with cancer carrying a DPYD variant allele (DPYD*2A, c.1236G>A, c.2846A>T, and c.1679T>G) were excluded. Univariable and multivariable logistic regression using predetermined predictors based on previous findings, including age, sex, body surface area, type of treatment regimen, and creatinine levels were used to develop the nomogram. The developed model was internally validated using bootstrap resampling and cross-validation. This model was not externally or clinically validated. A total of 2,147 DPYD wild-type patients with cancer treated with capecitabine-based chemotherapy regimens were included of which complete data of 1,745 patients were available and used for the development of the nomogram. Univariable and multivariable logistic regression showed that age, sex, and type of treatment regimen were strong predictors of severe capecitabine-related toxicity in DPYD wild-type patients. Internal validation demonstrated a concordance index of 0.68 which indicates a good discriminative ability for prediction of severe capecitabine-related toxicity. The developed nomogram includes readily available parameters and may be a helpful tool for clinicians to assess the risk of developing severe capecitabine-related toxicity in patients without known risk DPYD variant alleles treated with capecitabine-based anticancer regimens., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: DPYD -guided fluoropyrimidine dosing improves patient safety in carriers of DPYD variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis., Methods: Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% ( DPYD *2A and c.1679T>G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression., Results: In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G>A, 25 DPYD *2A, 13 c.2846A>T, and-when pooled-93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P = .698) were not negatively affected by DPYD -guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P = .007) was found in c.1236G>A variant carriers, whereas no differences were found for DPYD *2A and c.2846A>T carriers., Conclusion: In this exploratory analysis, DPYD -guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.

Background: The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors., Methods: GSK3174998 (0.003-10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity., Results: 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56-CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response., Conclusions: GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers., Trial Registration Number: NCT02528357., Competing Interests: Competing interests: SP-V is a principal/subinvestigator of clinical trials for AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argenx BVBA, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca A, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare AG, BBB Technologies BV, Beigene, BicycleTx Ltd, Bioalliance Pharma, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, GamaMabs, Genentech, GSK, H3 Biomedicine, Hoffmann La Roche AG, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma AS, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merus, Molecular Partners AG, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Plexxikon, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, and Xencor outside the submitted work; non-financial support (drug supplied) from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche; research funding from Boehringer Ingelheim, AstraZeneca, Roche, and Merck KGaA for projects unrelated to this manuscript. VL reports consulting for Takeda, Seattle Genetics, Bristol Myers Squibb, AstraZeneca, Guardant Health; research funding from GSK, Bristol Myers Squibb, Merck, Seattle Genetics. WR reports nothing to disclose. TMB reports consulting for Guardant Health, Loxo Pharmaceuticals, Pfizer, Exelixis, Blueprint Medicines, Foundation Medicine, Bayer, AstraZeneca, Ignyta, Moderna Therapeutics, Pfizer. Speakers Bureau: Bayer, Bristol Myers Squibb, and Lilly; research funding from Daiichi Sankyo, Medpacto, Inc., Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GSK, Novartis, Pfizer, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium Pharmaceuticals, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Aileron Therapeutics, Bristol Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Loxo, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Onyx, Phosplatin Therapeutics, Foundation Medicine, and ARMO BioScience; personal expenses from Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Pharmacyclics, Sysmex, and Pfizer. AHa reports research funding from Genentech/Roche, Merck, GSK, Bristol Myers Squibb, Novartis, Boston Biomedical, Boehringer Ingelheim, AstraZeneca/Medimmune Eisai; personal fees from Merck and GSK. DCC is a consultant for Nektar, Pfizer, Werewolf, and HUYA. FSH reports research funding from Bristol Myers Squibb and Novartis; receives personal fees from Bristol Myers Squibb, Merck, EMD Serono, Novartis, Surface, Compass Therapeutics, Apricity, Sanofi, Pionyr, Torque, Bicara, Checkpoint Therapeutics, Genentech/Roche, Bioentre, Gossamer, Iovance, Trillium, Catalym, Immunocore, Amgen, Kairos, Eisai, and Rheos. JHMS is a shareholder and part-time employee of Modra Pharmaceuticals BV and patent holder of oral taxanes; reports consulting for Debiopharm. JKL reports other from GSK, Novartis, Medivation/Pfizer, Genentech, EMD-Serono, AstraZeneca, Medimmune, Zenith, Ayala, UpToDate review panels for NCCN, ASCO, NIH PDQ, Medlearning, Physicians Education Resource, Prime Oncology, Medscape, Clinical Care Options, Medpage. SA reports advisory board participation for MSD, Sanofi, Roche, Bristol Myers Squibb, Pfizer; research support from Sanofi. KAA reports research funding (to institution) from Pfizer, AstraZeneca, Amgen, Trishula, GSK, Merck, and Eli Lilly. FO is a principal/subinvestigator of clinical trials for Amgen, AstraZeneca, Cytovation, GSK, Lilly, MSD, Revmed, Incyte, Boehringer Ingelheim, Bristol Myers Squibb, Roche/Genentech, Exelexis, Relay, and InterRNA. MM reports research funding from Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, Genentech, Gilead Sciences, GSK, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar, Novartis, Oncorus, PACT Pharma, Pfizer, Plexxikon, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock Seattle Genetics, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, and Xilio. M; consulting/advisory role for Astellas Pharma, AstraZeneca, BicycleTX Limited, Castle Biosciences, Eisai, Ideaya Biosciences, iTeos, Pfizer, and Regeneron Pharmaceuticals. NS reports consulting/advisory role for Deciphera, AADi, Blueprint Medicines, Bayer, Epizyme, and Boehringer Ingelheim; research funding from GSK, Karyopharm, Deciphera, Ascentage Pharma, Daiichi Sankyo/Lilly, and AstraZeneca/MedImmune. SC is the principal/subinvestigator of clinical trials for AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, AstraZeneca AB, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare AG, BBB Technologies BV, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Casi Pharmaceuticals, Inc, Celgene Corporation (a Bristol-Myers Squibb company), Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Cytovasion, Daiichi Sankyo, Debiopharm, Eisai, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, GamaMabs, Genentech, GSK, H3 Biomedicine, Hoffmann La Roche AG, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Medimmune, Menarini Ricerche, Merck, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners AG, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Relay Therapeutics, Inc, Roche, Sanofi Aventis, Seattle Genetics, Sotio, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene SA, Turning Point Therapeutics, and Xencor; reports research grants from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Pfizer, Roche, and Sanofi; reports non-financial support (drug supplied) from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, and Roche; reports honoraria from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, Janssen, Merck, Novartis and Roche; reports participation in advisory boards for Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, Ellipses Pharma, Oncovita, Seagen, UltraHuman8; reports travel and congress support from AstraZeneca, Bristol Myers Squibb, Merck, Ose Pharma, Roche, Sotio. MA reports research funding (to institution) from Genentech, Nektar Therapeutics, Merck, GSK, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, and Gilead. Advisory boards: GSK, Shattuck Lab, Bristol Myers Squibb, AstraZeneca; reports speaker fees from AstraZeneca, and Nektar Therapeutics. AS reports participation in advisory boards for Merck, Bristol Myers Squibb, Novartis, Oncorus, Janssen, Medison, and Immunocore; reports research support: Novartis, Bristol Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, Treadwell, and Amgen. OR reports employment with AstraZeneca; reports research funding from Merck; reports speaker for activities supported by educational grants from Bristol Myers Squibb and Merck; reports consulting for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi, Boehringer Ingelheim; reports pending patent for “Methods of using pembrolizumab and trebananib”. EMP, CMA, HZ, HS, SAG, MW, KMY, NY, and AHo report employment with GSK. MJC is an employee of Merck and owns stock. EVS is an employee of Merck. AM has been a principal or coinvestigator of clinical trials using OX40-targeted agents and/or has provided consulting services for Roche/Genentech, AstraZeneca, Pfizer, GSK, HiFiBiO, Bristol Myers Squibb, Shattuck Labs. JW reports consulting for Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, ImCheck, Sellas, Evaxion and EMD Serono; reports participation in advisory boards for Bristol Myers Squibb (compensated), CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and Neximmune; reports equity holdings in Biond, Evaxion, Instil Bio, OncoC4, and Neximmune; reports research support (to institution) from Bristol Myers Squibb, Merck, GSK, Moderna, Pfizer, Novartis, and AstraZeneca, Moffitt Cancer Center; reports patent for ipilimumab biomarker and tumor-infiltrating lymphocytes preparation and a PD-1 patent (Biodesix). JVH reports other from GSK, AstraZeneca, Checkmate Pharmaceuticals, Brightpath Biotherapeutics, Eli Lilly & Co, Kairos Venture Investments, Triptych Health Partners; reports patent with Spectrum Pharmaceuticals., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors., Patients and Methods: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly., Results: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC)., Conclusion: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers., Implications for Practice: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials., (© 2021 GlaxoSmithKline. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose-escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose-levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/mL d1/d22. After two cycles, patients continued olaparib 300 mg BID as monotherapy. Primary objective was to assess the maximum tolerable dose (MTD). Twenty-four patients with a confirmed diagnosis of advanced cancer were included. Most common adverse events were nausea (46%), fatigue (33%) and platelet count decrease (33%). Dose-level 3 (olaparib 75 mg BID and carboplatin AUC 4 mg*min/mL; n = 6) was defined as MTD. Fourteen out of 24 patients (56%) had a partial response as best response (RECIST 1.1). Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with olaparib tablet AUC 0-12 of 16.3 μg/mL*h at MTD. Polymers of ADP-ribose levels in peripheral blood mononuclear cells were reduced by 98.7% ± 0.14% at Day 8 compared to Day 1 for dose-level 3. Olaparib tablets 75 mg BID and carboplatin AUC 4 mg*min/mL for two cycles preceding olaparib monotherapy 300 mg is a feasible and tolerable treatment schedule for patients with advanced cancer., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity., Methods: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles., Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median T max 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients., Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing., Clinical Trial Registration: NCT02316197.

Background: The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor., Objective: Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints., Patients and Methods: Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors. Each treatment cycle lasted 21 days. The primary objective was to determine the maximum tolerated dose based on dose-limiting toxicities (DLTs) evaluated during cycle 1, and the recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity., Results: Overall, 180 patients received pimasertib (dose range 1-255 mg/day). DLTs were mainly observed at doses ≥ 120 mg/day and included skin rash/acneiform dermatitis and ocular events, such as serous retinal detachment. The most common drug-related adverse events were consistent with class effects, including diarrhea, skin disorders, ocular disorders, asthenia/fatigue, and peripheral edema. The median time to maximum pimasertib concentration was 1.5 h across dosing schedules, and the apparent terminal half-life was 5 h across qd dosing schedules. Pimasertib decreased ERK phosphorylation within 2 h of administration, which was maintained for up to 8 h at higher doses and prolonged with bid dosing., Conclusions: Based on the safety profile and efficacy signals, a continuous bid regimen was the preferred dosing schedule and the RP2D was defined as 60 mg bid., Trial Registration: ClinicalTrials.gov, NCT00982865.

Aims: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations., Methods: This Phase I open-label study assessed the PK, safety and tolerability of single doses of olaparib 300-mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child-Pugh class A) or moderate (MoHI; Child-Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long-term safety assessment., Results: Thirty-one patients received ≥1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least-squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56) vs those with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22) vs those with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected., Conclusion: Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI., (© 2020 The British Pharmacological Society.)

The US Food and Drug Administration (FDA) has four expedited programs, including the breakthrough therapy designation (BTD). Recently, this program has been criticized. In this feature, we determine whether BTD oncology drugs were truly a breakthrough, based on the outcome of a validated instrument to measure clinical benefit. We find that only a few drugs were likely a breakthrough, indicating that the success rate of the BTD program is somewhat low. Despite this, we believe that programs for fast drug approval do have a place in the current regulatory practice and that the necessary efforts for their improvement should be further explored, especially considering the remaining unmet medical need for patients with cancer., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1-2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications.

Background In the first part of this extensive phase I study (NCT00516724), continuous olaparib twice daily (bid) with carboplatin and/or paclitaxel resulted in myelosuppression and dose modifications. Here, we report the safety, tolerability, and efficacy of intermittent olaparib dosing combined with carboplatin and paclitaxel. Methods Patients with advanced solid tumors (part D) and enriched for ovarian and breast cancer (part E) received olaparib (capsule and tablet formulations) using intermittent schedules (2 to 10 days of a 21-day cycle) combined with carboplatin/paclitaxel. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs), and physical examinations. Pharmacokinetic assessments of olaparib capsule and tablet combined with carboplatin/paclitaxel were performed. Tumor responses (RECIST) were assessed every 2 cycles. Results In total, 132 heavily pre-treated patients were included. One DLT of grade 3 elevated alanine aminotransferase lasting for 8 days was reported (olaparib tablet 100 mg bid days 3-12, carboplatin area under the curve 4 and paclitaxel 175 mg/m 2 ). The most common hematological AEs were neutropenia (47%) and thrombocytopenia (39%), which frequently led to dose modifications. Non-hematological AEs were predominantly grade 1-2, including alopecia (89%) and fatigue (84%). Overall objective response rate was 46%. Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1-5).

Background and Objectives: MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate., Methods: MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial. Pharmacokinetic data were analyzed using non-linear mixed-effects modeling. Different compartmental models were evaluated. Various body size parameters including body weight, body surface area, and fat-free mass were evaluated as covariates in addition to age, sex, HER2 status, and tumor burden., Results: In total, 1115 serum concentration measurements were available from 116 patients. The pharmacokinetics of MCLA-128 was best described by a two-compartment model with linear and non-linear (Michaelis-Menten) clearance. Fat-free mass significantly affected the linear clearance and volume of distribution of the central compartment of MCLA-128, explaining 8.4% and 5.6% of inter-individual variability, respectively. Tumor burden significantly affected the non-linear clearance capacity. Simulations demonstrated that dosing based on body size parameters resulted in similar area under the plasma concentration-time curve for a dosing interval (AUC 0-τ ), maximum and trough concentrations of MCLA-128, compared to flat dosing., Conclusions: This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.

Purpose: Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy)., Methods: Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8., Results: A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m 2 /day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment., Conclusion: The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m 2 bi-daily on day 1-14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.

Background: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER)., Methods: In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336)., Results: Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC., Conclusions: Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.

Background: Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors., Methods: In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W)., Results: Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit., Conclusions: Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types., Trial Registration Number: NCT02404441., Competing Interests: Competing interests: AN received research funding from NCI, EMD Serono, MedImmune, Healios Oncology Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Regeneron, Merck, BMS, Pfizer, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and Immune Deficiency Foundation (spouse); travel/accommodation expense from ARMO BioSciences; and consultancy fees and research funding from CytomX Therapeutics and Novartis. JG received grant funding from Array, Tesaro, Moderna, Adaptimmune, and Alexo; personal fees from Oncorus, Regeneron, Pfizer, Incyte, Agios, Amgen, and Ironwood Pharmaceuticals; and grant funding and personal fees from Bristol-Myers Squibb, Genentech/Roche, Takeda, Blueprint, Loxo, Novartis, and Merck. PMF received research funding from Corvus and Kyowa; consultancy fees from AbbVie, Boehringer, EMD Serono, Inivata, Janssen, Lilly, and Merck; and research funding and consultancy fees from AstraZeneca, BMS, and Novartis. MOB received funding from Novartis, personal fees from BMS, Adaptimmune, GSK, Novartis, EMD Serono, Sanofi, Immunocore, and Turnstone; grant funding from Takara Bio; and personal fees and grant funding from Merck. C-CL received personal fees from BeiGene, Daiichi Sankyo, Roche, and Novartis. SS received research funding from GSK, Millennium, MedImmune, Johnson & Johnson, Gilead, Plexxikon, Onyx, Bayer, Blueprint, XuanZhu, Incyte, Toray, Celgene, Hengrui, OncoMed, Tesaro, AADi, Merck, Inhibrx, AMAL, and Syndax; personal fees and research funding from Novartis; equity from Iterion Therapeutics, Proterus Therapeutics, ConverGene, and Stingray Therapeutics; honoraria from Exelixis, Loxo Oncology, Natera, Hengrui Therapeutics, Tarveda Therapeutics, Dracen Pharmaceuticals, and Barricade Therapeutics; and owns stock with LSK BioPharma and Salarius Pharmaceuticals. MT received consultancy fees from Eisai, Bristol-Myers Squibb, Array Biopharma, Blueprint Medicines, Arqule, Loxo Oncology, Bayer, Novartis, and Genentech. JHMS received personal fees from Modra Pharmaceuticals. TMB received grant funding from Daiichi Sankyo, Medpacto, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millennium, Phosplatin Therapeutics, Calithera Biosciences, Kolltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Roche, Aileron Therapeutics, Bristol-Myers Squibb, Amgen, Onyx, Sanofi, Boehringer-Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, and ARMO Biosciences; grant funding and consultancy fees from Leap Therapeutics; grant funding, consultancy fees, and non-financial support from Ignyta and Moderna Therapeutics; grant funding, personal fees, and consultancy fees from Pfizer; grant funding, personal fees, and non-financial support from Loxo and Bayer; personal fees and non-financial support from Guardant Health; and personal fees from Exelesis. HW, HS, and JM are employees of Novartis. APS and JF are employees of Novartis and own stock with Novartis. SC is an employee of Novartis and has patents with Novartis., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To assess the proposed associations of the c.742-227G>A (rs2612091) polymorphism within the Enolase Superfamily Member 1 gene (ENOSF1) and two variants in the adjacent Thymidylate Synthase gene (TYMS): the 5'VNTR 28bp-repeat (rs45445694) and 3'UTR 6bp-indel (rs11280056) with severe toxicity in fluoropyrimidine-treated cancer patients, we performed an individual patient data meta-analysis. Only studies investigating all three-abovementioned variants with fluoropyrimidine-related toxicities were considered for meta-analysis. Associations were tested individually for each study using multivariate regression. Meta-analysis was performed using a random-effects model. One-stage multivariate regressions including tests for independent SNP effects were applied to investigate individual effects of the variants. Multivariate haplotype regression analyses were performed on a pooled dataset to test multi-SNP effects. Of four studies including 2'067 patients, 1'912 were eligible for meta-analysis. All variants were exclusively associated with severe hand-foot-syndrome (HFS) (TYMS 2R: OR = 1.50, p = 0.0002; TYMS 6bp-ins: OR = 1.42 p = 0.0036; ENOSF1 c.742-227G: OR = 1.64 p < 0.0001, per allele). We observed independent effects for ENOSF1 c.742-227G>A and the TYMS 28bp-repeat: each toxicity-associated allele increased the risk for severe HFS (OR = 1.32 per allele, p < 0.0001). Patients homozygous for both variants were at the 3-fold higher risk for severe HFS compared to wild-type patients. Our results confirm an essential role for ENOSF1 c.742-227G and TYMS 2R-alleles in the development of fluoropyrimidine-related HFS. This suggests an important function of these genes in the development of severe HFS. Furthermore, these variants might help stratify patients in studies investigating measures of HFS prevention., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-β-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients., (© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule was investigated., Patients and Methods: Patients with metastatic solid tumors were included. Dose escalation was performed using a classical 3+3 design. Pharmacokinetic sampling was performed for up to 48 hours after drug administration. Safety was evaluated using CTCAE v3.0. Antitumor activity was assessed according to RECIST v1.0., Results: Sixty-seven patients were treated at weekly docetaxel dosages ranging from 30 to 80 mg in combination with 100- or 200-mg ritonavir. Most common toxicities were nausea, vomiting, diarrhea and fatigue, mostly of grade 1-2 severity. No hypersensitivity reactions were observed. The area under the plasma concentration-time curve (AUC 0-48 ) of docetaxel at the RP2D of once-weekly 60-mg ModraDoc001 capsule with 100-mg ritonavir was 1,000 ± 687 ng/mL/hour and for once-weekly 60-mg ModraDoc006 tablet with 100-mg ritonavir, the AUC 0-48 was 1,790 ± 819 ng/mL/hour. Nine partial responses were reported as best response to treatment., Conclusions: Oral administration of once-weekly docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir is feasible. The RP2D for both formulations is 60-mg ModraDoc with 100-mg ritonavir. Antitumor activity is considered promising., (©2019 American Association for Cancer Research.)

Background: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations., Methods: This phase I open-label study assessed the pharmacokinetics, safety and tolerability of single-dose, oral 300-mg olaparib tablets in adults (aged 18-75 years) with solid tumours. Patients had normal renal function, or mild or moderate renal impairment (estimated creatinine clearance ≥ 81, 51-80 or 31-50 mL/min, respectively). Blood was collected for 96 h, and urine samples collected for 24 h post-dose. Patients could continue taking olaparib 300 mg twice daily for a long-term safety assessment., Results: Overall, 44 patients received one or more doses of olaparib and 38 were included in the pharmacokinetic assessment. Patients with mild renal impairment had an area under the curve geometric least-squares mean ratio of 1.24 (90% confidence interval 1.06-1.47) and a geometric least-squares mean maximum plasma concentration ratio of 1.15 (90% confidence interval 1.04-1.27) vs. those with normal renal function. In patients with moderate renal impairment, the geometric least-squares mean ratio for the area under the curve was 1.44 (90% confidence interval 1.10-1.89) and for the maximum plasma concentration was 1.26 (90% confidence interval 1.06-1.48) vs. those with normal renal function. No new safety signals were detected in patients with mild or moderate renal impairment., Conclusions: In patients with mild renal impairment, the small increase in exposure to olaparib was not considered clinically relevant. In patients with moderate renal impairment, exposure to olaparib increased by 44%; thus, these patients should be carefully monitored and the tablet dose should be adjusted to 200 mg twice daily., Clinical Trials Registration: NCT01894256.

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed in which for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade ≥ 3) treatment-related toxicity was compared to 1] a cohort of 1606 wild-type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, p = 0.47) nor progression-free survival (median 14 months versus 10 months, p = 0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, p = 0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (p < 0.001). Our study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety., (© 2018 UICC.)

The incidence of neutropenia in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta-analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta-analysis was conducted of studies which reported areas under the plasma concentration-time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta-analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5-2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2-fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31-0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Immunotherapy with monoclonal antibodies targeting the programmed-death-1 (PD-1) receptor has become standard of care for an increasing number of tumor types. Pharmacokinetic studies may help to optimize anti-PD-1 therapy. Therefore, accurate and sensitive determination of antibody concentrations is essential. Here we report an enzyme linked immunosorbent assay (ELISA) capable of measuring nivolumab and pembrolizumab concentrations in serum and cerebrospinal fluid (CSF) with high sensitivity and specificity. The assay was developed and validated based on the specific capture of nivolumab and pembrolizumab by immobilized PD-1, with subsequent enzymatic chemiluminescent detection by anti-IgG4 coupled with horse radish peroxidase (HRP). The lower limit of quantification for serum and CSF was 2 ng/mL for both anti-PD-1 agents. The ELISA method was validated and showed long term sample stability of >1 year. This method is reliable, relatively inexpensive and can be used in serum and CSF from pembrolizumab and nivolumab treated patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics and pharmacodynamics of combination therapy with the HDM2 inhibitor SAR405838 and the MEK1/2 inhibitor pimasertib administered orally once daily (QD) or twice daily (BID) in locally advanced or metastatic solid tumours (NCT01985191)., Methods: Patients with locally advanced or metastatic solid tumours with documented wild-type TP53 and RAS or RAF mutations were enroled. A 3 + 3 dose-escalation design was employed. The primary objective was to assess maximum tolerated dose (MTD)., Results: Twenty-six patients were treated with SAR405838 200 or 300 mg QD plus pimasertib 60 mg QD or 45 mg BID. The MTD was SAR405838 200 mg QD plus pimasertib 45 mg BID. The most common dose-limiting toxicity was thrombocytopenia. The most frequently occurring treatment-related adverse events were diarrhoea (81%), increased blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). No significant drug-drug interactions were observed. The biomarkers MIC-1 and pERK were, respectively, upregulated and downregulated in response to study treatment. In 24 efficacy-evaluable patients, one patient (4%) had a partial response and 63% had stable disease., Conclusions: The safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed.

Background: Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved survival compared with previous standards of care for several tumor types. Although proven to be successful in more immunogenic tumors, ICB is still largely ineffective in patients with tumors that are not infiltrated by immune cells, the so-called cold tumors., Patients and Methods: This review describes the effects of different chemotherapeutic agents on the immune system and the potential value of these different types of chemotherapy as combination partners with ICB in patients with solid tumors. Both preclinical data and currently ongoing clinical trials were evaluated. In addition, we reviewed findings regarding different dosing schedules, including the effects of an induction phase and applying metronomic doses of chemotherapy., Results: Combining ICB with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to ICB monotherapy. Chemotherapy, that was originally thought to be solely immunosuppressive, can exert immunomodulatory effects which may be beneficial in combination with immunotherapy. Each chemotherapeutic drug impacts the tumor microenvironment differently, and in order to determine the most suitable combination partners for ICB it is crucial to understand these mechanisms., Conclusion: Preclinical studies demonstrate that the majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, for certain chemotherapeutic agents timing, dose and sequence of administration of chemotherapeutic agents and ICB is important. Further studies should focus on determining the optimal drug combinations, sequence effects and optimal concentration-time profiles in representative preclinical models., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel., Methods: PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model., Results: In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age., Conclusion: In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.

Background: Fluoropyrimidine therapy including capecitabine or 5-fluorouracil can result in severe treatment-related toxicity in up to 30% of patients. Toxicity is often related to reduced activity of dihydropyrimidine dehydrogenase, the main metabolic fluoropyrimidine enzyme, primarily caused by genetic DPYD polymorphisms. In a large prospective study, it was concluded that upfront DPYD-guided dose individualisation is able to improve safety of fluoropyrimidine-based therapy. In our current analysis, we evaluated whether this strategy is cost saving., Methods: A cost-minimisation analysis from a health-care payer perspective was performed as part of the prospective clinical trial (NCT02324452) in which patients prior to start of fluoropyrimidine-based therapy were screened for the DPYD variants DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A and received an initial dose reduction of 25% (c.2846A>T, c.1236G>A) or 50% (DPYD*2A, c.1679T>G). Data on treatment, toxicity, hospitalisation and other toxicity-related interventions were collected. The model compared prospective screening for these DPYD variants with no DPYD screening. One-way and probabilistic sensitivity analyses were also performed., Results: Expected total costs of the screening strategy were €2599 per patient compared with €2650 for non-screening, resulting in a net cost saving of €51 per patient. Results of the probabilistic sensitivity and one-way sensitivity analysis demonstrated that the screening strategy was very likely to be cost saving or worst case cost-neutral., Conclusions: Upfront DPYD-guided dose individualisation, improving patient safety, is cost saving or cost-neutral but is not expected to yield additional costs. These results endorse implementing DPYD screening before start of fluoropyrimidine treatment as standard of care., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: Pharmacokinetics of small molecule kinase inhibitors (KIs) used in cancer treatment may alter with increasing age, but results are conflicting. This study aims to compare exposure to KIs between older and younger patients (≥70 and <70 years) in clinical practice., Methods: KI plasma concentrations of routinely treated patients were measured using validated assays. Calculated trough concentrations were compared in both age groups. For KIs with a clinically meaningful target concentration (erlotinib, imatinib, pazopanib, sunitinib and vemurafenib), influence of older age on target attainment was assessed., Results: We analysed 616 samples from 454 patients (median age: 61; range 20-93 years), treated with dabrafenib (n = 105), erlotinib (n = 49), imatinib (n = 165), pazopanib (n = 63), sunitinib (n = 87), trametinib (n = 95) and vemurafenib (n = 52). Older age did not significantly influence exposure to erlotinib, imatinib, pazopanib, sunitinib, trametinib and vemurafenib. Elderly patients had significantly higher dabrafenib trough concentrations than younger patients (P = 0.02; 62 ng ml -1 (coefficient of variation [CV] 41%), vs. 53 ng ml -1 (CV 46%), respectively). For KIs with a predefined target concentration, 68% of older and 61% of younger patients reached target., Conclusions: In this real-world study, exposure to most included KIs was comparable in older and younger patients, except for dabrafenib, which showed higher exposure in older patients. In the absence of an absolute target for this KI, clinical relevance remains unclear. For all other included KIs, our data suggest no clinically relevant influence of older age on KI exposure., (© 2018 The British Pharmacological Society.)

Background: Prospective DPYD genotyping prevents severe fluoropyrimidine (FP)-induced toxicity by decreasing dosages in DPYD variant allele carriers. FP dosages in chemoradiation therapy (CRT) are lower than those in other FP-containing regimens. Pharmacogenetic guidelines do not distinguish between regimens, leaving physicians in doubt to apply dose reductions. Our aim was to investigate severe toxicity in DPYD variant allele carriers receiving CRT., Methods: Medical records of 828 patients who received FP-based CRT were reviewed from three centres. Severe (grade ≥III) toxicity in DPYD variant allele carriers receiving upfront FP dose reductions according to pharmacogenetic dosing guidelines and DPYD variant allele carriers not receiving FP dose reductions was compared with DPYD wild-type patients receiving standard dose of FPs in CRT., Results: DPYD variant allele carriers treated with standard dosages (N = 34) showed an increased risk of severe gastrointestinal (adjusted OR = 2.58, confidence interval [CI] = 1.02-6.53, P = 0.045) or severe haematological (adjusted OR = 4.19, CI = 1.32-13.25, P = 0.015) toxicity compared with wild-type patients (N = 771). DPYD variant allele carriers who received dose reductions (N = 22) showed a comparable frequency of severe gastrointestinal toxicity compared with wild-type patients, but more (not statistically significant) severe haematological toxicity. Hospitalisations for all DPYD variant allele carriers were comparable, independent of dose adjustments; however, the mean duration of hospitalisation was significantly shorter in the dose reduction group (P = 0.010)., Conclusions: Standard FP dosages in CRT resulted in an increased risk of severe toxicity in DPYD variant allele carriers. We advise to apply FP dose reductions according to current guidelines in DPYD variant allele carriers starting CRT., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care., Methods: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete., Findings: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers., Interpretation: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care., Funding: Dutch Cancer Society., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors. Patients and Methods: Part 1 ( n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 ( n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486. Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days. Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072-80. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14 C-plitidepsin with a maximum radioactivity of 100 µCi., Methods: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC)., Results: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces., Conclusion: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.

Purpose: AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet., Methods: Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and C max ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2)., Results: In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and C max were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later t max and lower C max after food versus overnight fast. Fed and fasted AUCτ and C max ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states., Conclusions: PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

Purpose: Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1-3, FGFR 1-3, and PDGFR. This study was performed to investigate the potential drug-drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors., Methods: Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine., Results: Forty-five patients were enrolled; 24 were evaluable for drug-drug interaction assessment. Median age was 60 years (range 30-85). At steady state the geometric mean for dovitinib (coefficient of variation%) of the area under the plasma concentration-time curve (AUC 0-72h ) and maximum concentration (C max ) were 2880 ng/mL h (47%) and 144 ng/mL (41%), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC 0-72h and C max were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC 0-72h and C max (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90% confidence interval (CI) 2.58, 3.20] and 1.80 (90% CI 1.66, 1.95). This effect is considered a moderate drug-drug interaction., Conclusions: Fluvoxamine co-administration resulted in a 80% increase in C max and a 188% increase in AUC 0-72h of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.

Background: Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors., Materials and Methods: A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1. The primary objectives of the study were to assess safety and tolerability, identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose, and identify the recommended phase II dose (RP2D). Evaluation of a dose-expansion cohort at the RP2D was performed., Results: Fifty-seven patients were treated in the study. All patients experienced at least one adverse event (AE). Grade ≥3 AEs, serious AEs, and deaths were reported in 38 (66.7%), 19 (33.3%), and 4 (7.0%) patients, respectively. DLTs occurred in nine patients across eight cohorts and the RP2D was determined to be 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib. Two patients (3.5%) experienced partial response and 19 (33.3%) had stable disease., Conclusion: Combining pictilisib with erlotinib in patients with advanced solid tumors is feasible; however, antitumor activity is limited. Additional studies may identify patients likely to benefit from combined inhibition of EGFR and PI3K pathways., Implications for Practice: Combining drugs targeting different signaling pathways in cancer growth and survival could overcome drug resistance and improve antitumor activity. In this first-in-human study for the combination, addition of the PI3K inhibitor pictilisib to the EGFR tyrosine kinase inhibitor erlotinib resulted in toxicity that led to dose and schedule modifications to identify a tolerable recommended phase II dose of 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib daily. The limited antitumor activity observed, however, suggests that additional studies are needed to identify patients most likely to benefit from combined EGFR and PI3K inhibition., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Two solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored., Methods: Adult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0., Results: ModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1-2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration-time curve (AUC 0-48 ) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment., Conclusion: Oral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. In total, a mean of 77.4% of the administered radioactivity was excreted over a time period of 20 days, of which 71.3% was recovered in faeces and 6.1% was found in urine. The majority excreted in urine was accounted for by unchanged plitidepsin, with only 1.5% of the total administered dose explained by metabolites in urine. Faeces, on the other hand contained low levels of parent compound, which means that most of the TRA excreted in faeces was accounted for by metabolites. TRA levels were 3.7 times higher in whole blood compared to plasma. Plitidepsin was widely distributed and plasma clearance was low. This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion.

Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas. Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non-small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib. Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR. Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406-15. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Recent literature reviews and registration documents covering novel Signal Transduction Inhibitors in the treatment of cancer paint a picture of inefficiency and variability, where formulation improvements could be valuable. In this article, we discuss apparent drug design flaws as we impose the current standard formulation practice.

Wee1 is a protein kinase that regulates the G 2 checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDK) are a family of 14 serine/threonine protein kinases that coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G 2 into mitosis. There are two mechanisms by which the G 2 checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of the Wee1 kinase, which phosphorylates Cdc2. Blockade at the G 2 checkpoint is especially important for p53-mutant cells because these tumors mainly rely on DNA repair at the G 2 checkpoint. AZD1775 (formerly MK-1775) is a small-molecule, pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging antitumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents. Promising combination schedules are being investigated at the moment, for example, combining PARP inhibition and Wee1 inhibition. Also, a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the antitumor effect. Clin Cancer Res; 23(16); 4540-4. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors. Methods This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/m 2 14 C-vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168 h after injection or until recovered radioactivity over 24 h was less than 1% of the administered dose (whichever was earlier). Total radioactivity (TRA), vosaroxin and metabolites were studied in all matrices. Results Unchanged vosaroxin was the major species identified in plasma, urine, and feces. N-desmethylvosaroxin was the only circulating metabolite detected in plasma, accounting for <3% of the administered dose. However, in plasma, the combined vosaroxin + N-desmethylvosaroxin AUC 0-∞ was 21% lower than the TRA AUC 0-∞ , suggesting the possible formation of protein bound metabolites after 48 h when the concentration-time profiles diverged. The mean recovery of TRA in excreta was 81.3% of the total administered dose; 53.1% was excreted through feces and 28.2% through urine. Conclusions Unchanged vosaroxin was the major compound found in the excreta, although 10 minor metabolites were detected. The biotransformation reactions were demethylation, hydrogenation, decarboxylation and phase II conjugation including glucuronidation.

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.

Background: We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study., Methods: Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS (TYMS 5'-UTR VNTR and TYMS 3'-UTR 6-bp ins/del) were measured and tested for associations with severe fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q<0.050 (corresponding to P<0.010)., Results: Uracil was superior to the dihydrouracil/uracil ratio as a predictor of severe toxicity. High pretreatment uracil concentrations (>16 ng ml -1 ) were strongly associated with global severe toxicity (OR 5.3, P=0.009), severe gastrointestinal toxicity (OR 33.7, P<0.0001), toxicity-related hospitalisation (OR 16.9, P<0.0001), as well as fatal treatment-related toxicity (OR 44.8, P=0.001). None of the DPYD variants alone, or TYMS variants alone, were associated with severe toxicity., Conclusions: High pretreatment uracil concentration was strongly predictive of severe, including fatal, fluoropyrimidine-associated toxicity, and is a highly promising phenotypic marker to identify patients at risk of severe fluoropyrimidine-associated toxicity.

The spiraling cost of new drugs mandates a fundamentally different approach to keep lifesaving therapies affordable for cancer patients. We call here for the formation of new relationships between academic drug discovery centers and commercial partners, which can accelerate the development of truly transformative drugs at sustainable prices., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In recent years (2010-present) there has been an increase in the number of publications reporting the development, validation and use of bioanalytical methods in the rapidly expanding drug class of small molecule protein kinase inhibitors. Most reports describe the technological set-up of the methods that have allowed for drug concentration measurements from various sample types. This includes plasma, dried blood-spot, and tissue-analysis. Also method development, exploration of various techniques, as well as measurement and identification of metabolites were addressed. For the bioanalysis, a variety of sample-pretreatment methods like protein-precipitation, liquid-liquid extraction, and solid-phase extraction have been employed, all varying in complexity, cleanliness and time-consumption. Chromatographic separation, nowadays, is more focused on separating components from ion-suppressive effects, since for MS/MS detection, various components do not have to be baseline separated. For detection multiple types of detectors were used, ranging from state-of-the-art high resolution, and tandem mass spectrometry with low picogram per milliliter detection limits to the classical UV-detector with several nanograms per milliliter limits. As new bioanalytical methods have arisen that do rely on chromatographic separation, for example for high-throughput analysis, these are addressed in this review as well., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anticancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments., Patients and Methods: A pooled analysis of PK data was carried out for pregnant (Pr) and nonpregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently, we derived optimized dose regimens aiming to match to the area under the concentration-time curve (AUC) in nonpregnant patients., Results: The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of <1.32, <2.08, <1.37 and <4.21, respectively, with adequate precision [relative standard error (RSE) <37%]. For doxorubicin, no gestational effect could be estimated on clearance (CL). For epirubicin, docetaxel and paclitaxel, a fold-change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were, respectively, estimated on CL. Calculated dose adjustment requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (<4.2%) except for paclitaxel (-21.4%)., Conclusion: Clinicians should be aware of a decrease in drug exposure during pregnancy and should not a priori reduce dose. The decrease in exposure was most apparent for docetaxel and paclitaxel which is supported by known physiological changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Blocking both receptor and ligand of the vascular endothelial growth factor (receptor) VEGF(R) pathway might be feasible and increase antitumor activity. This phase I study investigated telatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, combined with bevacizumab, in adults with solid tumors., Patients and Methods: Twenty-six patients were treated in successive cohorts with telatinib (twice-daily continuously, 450-900 mg) or bevacizumab (bi-weekly, starting dose 5 mg/kg). Safety, pharmacokinetics, endothelial (progenitor) cell (E(P)C)/growth factor kinetics and efficacy were assessed., Results: Most frequent adverse events were pain, nausea, voice changes and fatigue. Five dose-limiting toxicities (DLTs) occurred: hypertension (cohort I and II), bowel perforation, lipase increase and atrial flutter (cohort III). Cumulative toxicity resulted in a bevacizumab dose reduction to 1 mg/kg (cohort III). Due to three DLTs (n = 14), this cohort represented the best-tolerated dose level. Bevacizumab effectively neutralized plasma VEGF even at 1 mg/kg. Twelve patients had stable disease (clinical benefit 46%). EPC and SDF-1α levels increased during monotherapy telatinib., Conclusions: Telatinib (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional toxicity impedes long-term treatment of patients. Therefore, this combination will not be pursued in a phase II setting.

Background: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules., Patients and Methods: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects., Results: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends., Conclusions: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.