Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH).

BACKGROUND: This phase I dose de-escalation study aimed to assess the tolerability, safety, pharmacokinetics (PK), and efficacy of sequentially decreasing doses of sorafenib in combination (SAM) with atorvastatin (A, 10 mg) and metformin (M, 500 mg BD) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients were enrolled in 1 of 4 sequential cohorts (10 patients each) of sorafenib doses (800 mg, 600 mg. 400 mg, and 200 mg) with A and M. Progression from one level to the next was based on prespecified minimum disease stabilization (at least 4/10) and upper limits of specific grade 3-5 treatment-related adverse events (TRAE). RESULTS: The study was able to progress through all 4 dosing levels of sorafenib by the accrual of 40 patients. Thirty-eight (95%) patients had either main portal vein thrombosis or/and extra-hepatic disease. The most common grade 3-5 TRAEs were hand-foot-syndrome (grade 2 and grade 3) in 3 (8%) and transaminitis in 2 (5%) patients, respectively. The plasma concentrations of sorafenib peaked at 600 mg dose, and the concentration threshold of 2400 ng/mL was associated with higher odds of achieving time to exposure (TTE) concentrations >75% centile (odds ratio [OR] = 10.0 [1.67-44.93]; P = .01). The median overall survival for patients without early hepatic decompensation (n = 31) was 8.9 months (95% confidence interval [CI]: 3.2-14.5 months). CONCLUSION: The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600 mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID: CTRI/2018/07/014865).

Role of ADME gene polymorphisms on imatinib disposition: results from a population pharmacokinetic study in chronic myeloid leukaemia.

PURPOSE: Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants. METHODS: Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib. RESULTS: Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous. CONCLUSION: Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.

Safety and CSF distribution of high-dose erlotinib and gefitinib in patients of non-small cell lung cancer (NSCLC) with brain metastases.

PURPOSE: Patients of non-small cell lung cancer (NSCLC) with brain metastases have limited treatment options. High-dose erlotinib (HDE) and gefitinib (HDG) have been tried in the past. This study investigates the cerebrospinal fluid (CSF) disposition and safety of both, high-dose erlotinib and gefitinib regimens. METHODS: Eleven and nine patients were treated with erlotinib and gefitinib, respectively. All patients received 1 week of standard dose of erlotinib (150 mg OD) or gefitinib (250 mg OD), followed by the high dose (1500 mg weekly for erlotinib and 1250 mg OD for gefitinib) from day 8. Blood and CSF samples were collected on days 7 and 15, 4 h after the morning dose and drug levels determined using LC-MS/MS. Adverse events were documented as per CTCAE 4.03 till day 15. RESULTS: Pulsatile HDE and daily HDG resulted in 1.4- and 1.9-fold increase in CSF levels, respectively. A constant 2% CSF penetration rate was observed across both doses of erlotinib, while for gefitinib the penetration rate for high dose was half that of the standard dose suggesting a nonlinear disposition. Three patients on HDE treatment discontinued treatment after the first dose due to intolerable toxicities, whereas HDG was better tolerated with no treatment discontinuations. Since CSF disposition of gefitinib followed saturable kinetics, a lower dose of 750 mg was found to achieve CSF concentrations comparable to that of the 1250 mg dose. CONCLUSIONS: HDG was better tolerated than HDE. CSF disposition of gefitinib was found to be saturable at a higher dose. Based on these findings, the dose of 750 mg OD should be considered for further evaluation in this setting.

Covid Antibody Titers in Cancer Patients Following Vaccination with ChAdOx1 nCOV-19 Vaccine.

Dr. Vikram GotaCovid-19 has led to significant mortality worldwide, with an increased risk in cancer patients. Vaccination provides significant protection against the infection. The study focuses on the immunogenicity and effectiveness of ChAdOx1 nCoV-19 vaccine in cancer patients within a real-world setting. Blood samples for measuring Covid antibody titers against the receptor binding domain were collected according to a convenient sparse sampling strategy in a real-world setting, with the days of the collection coinciding with their hospital appointment. The antibody titers between different groups were analyzed descriptively. A total of 56 patients were enrolled in the study. There was no apparent effect in antibody titers between patients with solid tumors and hematological malignancies (mean ± standard deviation [SD]: 36.80 ± 41.18 vs. 52.02 ± 26.27), among patients who were undergoing chemotherapy, immunotherapy, or local therapy (mean ± SD: 42.50 ± 44.46 vs. 50.06 ± 51.39 vs. 28.70 ± 25.03), and in patients with up to 90 days and more than 90 days' interval between their last treatment and date of vaccination (mean ± SD: 38.96 ± 42.66 vs. 40.51 ± 38.65). Additionally, there were only 2/56 patients with breakthrough infection, which points out the effectiveness of this vaccine in cancer patients. The ChAdOx1 nCoV-19 vaccine has activity in cancer regardless of the tumor type, type of treatment, or time from the last treatment.

Effect of body mass index on pharmacokinetics of paclitaxel in patients with early breast cancer.

BACKGROUND: Paclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients. METHODS: Early breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18-24.9 kg/m2 and overweight/obese, ≥25 kg/m2 , respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software. RESULTS: Eighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2 , mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two-sample t-test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2-sample t-test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, -0.009; p > 0.05). CONCLUSION: When dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under-dosing of this drug. TRIAL REGISTRATION: This study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.

ADME gene polymorphisms do not influence the pharmacokinetics of docetaxel: Results from a population pharmacokinetic study in Indian cancer patients.

BACKGROUND: Pharmacokinetics (PK) of docetaxel is characterized by high inter-individual variability (IIV). While covariate models that explain the PK variability of docetaxel exist, not much is known about the effects of genetic variations on docetaxel disposition. METHODS: Fifty patients with head and neck or prostate cancer were enrolled of whom two patients withdrew consent before the start of the study. Docetaxel was administered at either 50 or 75 mg/m2 as intravenous infusion over 1 h. One pharmacogenetic sample and a series of PK samples, either intensive (N = 5; 13 samples each) or sparse (N = 43; 6 samples each), were collected from each patient. Docetaxel levels were estimated using a validated HPLC method. Polymorphic loci on the Absorption, Distribution, Metabolism, and Elimination (ADME) genes were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. RESULTS: Docetaxel PK was well characterized by a three-compartment model. Clearance (Cl) was found to be 18 L/h with an IIV of 45.3%. None of the genetic variants showed significant covariate effect on the Cl of docetaxel. Patients with abnormal alanine aminotransferase (ALT) were found to have 25% lower Cl as compared to patients with normal ALT values. However, the covariate effect could not be established in the final model possibly due to lack of adequate number of patients with abnormal ALT. CONCLUSION: Genetic polymorphisms in the ADME gene do not explain the IIV in PK of docetaxel. However, patients with abnormal liver function might require dose reduction. CLINICAL TRIAL REGISTRATION: Not applicable since participants in this study received treatment that was standard of care.

Prognostic significance of pretreatment sodium levels in patients of nonsmall cell lung cancer treated with pemetrexed-platinum doublet chemotherapy.

BACKGROUND: Recent studies have shown pretreatment sodium level to be a predictive and prognostic marker in nonsmall cell lung cancer (NSCLC) patients treated with erlotinib. The objective of this study was to evaluate the prognostic significance of pretreatment sodium levels on progression-free survival (PFS) and overall survival (OS) in patients of NSCLC treated with pemetrexed-platinum doublet chemotherapy. PATIENTS AND METHODS: Stage IIIb/IV NSCLC patients aged ≥18 years for whom baseline serum sodium level was available were included in this retrospective study. All patients received standard pemetrexed-cisplatin/carboplatin doublet for six cycles followed by maintenance pemetrexed till progression. Electronic medical record database of our hospital was used to retrieve demographic data, pretreatment sodium levels, and survival data. Normal serum sodium (NSS) was defined as serum sodium ≥136 mEq/L, and low serum sodium (LSS) was defined as serum sodium <136 mEq/L. The impact of sodium levels on PFS and OS after adjusting other prognostic factors was estimated using Cox proportional hazard model. RESULTS: Data were available for 257 patients (male/female = 182/75) with median age of 55 (21-78) years. A total of 120 (46%) patients had LSS whereas 137 (54%) had NSS. Patients with NSS had significantly longer median PFS (7 months vs. 6 months; P < 0.05) and OS (16 months vs. 11 months; P < 0.05) compared to LSS group. Multivariate analysis showed LSS as an independent prognostic variable for poor survival (hazard ratio = 2.07, 95% confidence interval = 1.11-3.84). CONCLUSION: Pretreatment serum sodium level is an important prognostic marker in Stage IIIb/IV NSCLC patients. The simple possibility of testing coupled with low cost makes it an attractive biomarker.