Outcome of Topiramate in Migraine Prophylaxis

Background: Topiramate is an anti epileptic medication originally and one of the first line drugs for migraine prophylaxis.Objective: To assess outcome of Topiramate in migraine prophylaxis by evaluating reduction in frequency and/or severity of attacks and address most common adverse affect associated with it.Methods: A Descriptive, prospective hospital based study was conducted at Ibrahim Malik Hospital, National center of neurological disease and sciences within the period of October 2018 –May 2019. Data entered, cleaned, analyzed using SPSS version 25.0.Results: This study covered 32 study participants; the mean age (33 ± 10) years, with female predominance by 27 (84%).Nearly, half of them 15(47%) migraine triggered by weather changes, 13 (41%) menstruation. 17(53%) was suffering from headache > 24 months, and most of them 26(81%) used the OTC medications in the acute pain headache.Mean of frequency of attacks per month was reduce (6.1 base line to 3.2), in severity mean was (6.9 turn to 5). Reduction in Frequency of attacks there was significant in both number and severity (p value < 0.001) with no significant difference in (50 mg and 100mg dose). Concerning adverse effects 5(15.6%) didn’t complain of any, more than third 12(38%) experienced weight loss, 7(22%) both Abdominal/GIT symptoms and Dizziness, 5(16%) mood changes, 4(13%) both parathesia and decreased memory, 3(9%) both Anorexia and sleepiness.Conclusion: Topiramate is effective in reducing headache frequency and reasonably well tolerated in adult Sudanese patients with episodic migraine. This may provide good evidence to support its use in routine clinical management.

Association of losartan use with outcomes in metastatic pancreatic cancer patients treated with chemotherapy.

e16738 Background: A phase II trial has shown improved efficacy of neoadjuvant therapy when combined with losartan (by remodeling desmoplasia) in locally advanced pancreatic ductal adenocarcinoma (PDA). However, role of losartan is unknown in metastatic PDA. We examined the relationship between the use of the angiotensin II receptor antagonist, losartan, at time of diagnosis with clinical outcomes in metastatic PDA pts that received chemo. Methods: We retrospectively evaluated 114 metastatic PDA pts treated at our center between Jan 2000 and Nov 2019. We compared OS, PFS, objective response rate (ORR), and disease control rate (DCR) between pts using losartan at time of cancer diagnosis and a control group of pts not on losartan. A subanalysis was performed based on losartan dose: 100mg dose versus control pts. and based on chemo: FOLFIRINOX or gemcitabine+abraxane. Results: Table shows baseline demographics. No significant difference was found in OS [p = 0.455] or PFS [p = 0.919] in pts on losartan (median 274d, 83d) vs control (median 279d, 111d) [p = 0.466]. No significant difference was found in ORR [p = 0.621] or in DCR [p = 0.497]. No significant difference was found in OS [p = 0.771] or PFS [p = 0.064] in losartan pts (median 347d, 350d) vs control (median 333d, 101d) treated with FOLFIRINOX. No significant difference was found in OS [p = 0.916] or PFS [p = 0.341] in losartan (median 312d, 69d) vs control (median 221d, 136d) [p = 0.916] treated with gemcitabine+abraxane. No significant difference was found in OS [p = 0.727] or PFS [p = 0.790] in 100mg losartan pts (median 261d, 84d) vs control (median 279d, 111d). Conclusions: Pts on losartan at time of diagnosis had no significant difference in OS, PFS, ORR, DCR than control pts. However, a subanalysis of pts treated with FOLFIRINOX revealed a longer PFS with losartan than control but did not meet statistical significance, likely due to small sample size. To confirm if the benefit of losartan + FOLFIRINOX seen in neoadjuvant setting for locally advanced cancer also applies to metastatic cancer, our findings need to be validated in a larger cohort. [Table: see text]

Differential Alemtuzumab Dosage Effects in T-Cell Deplete Allogeneic Haematopoietic Stem Cell Transplants for Myeloid Malignancies- King's College Hospital London Experience

Introduction Alemtuzumab is a monoclonal anti-CD52 antibody, a pan-lymphodepleting immunosuppressive agent in common use as part of conditioning for allogeneic stem cell transplantation (Allo-HSCT) in United Kingdom and many other centres across the globe, with benefits related to reduced graft versus Host disease (GVHD) and lower non-relapse mortality (NRM). However, evidence for effective dose schedule in Allo-HSCT remains debatable with some concerns related to delayed immune reconstitution and increased relapses with higher dosages; but increased risk of acute and chronic GVHD observed with lower doses. We present a large single-centre UK experience evaluating differential dosage effect of Alemtuzumab on HSCT outcomes. Methods: We retrospectively evaluated 330 patients undergoing Allo-HSCTs for myeloid malignancies (AML/MDS/MPNs) during a 10-year period (Jan 2010 to April 2019) at King's College Hospital, London. Two dosage schedules of Alemtuzumab based T-cell deplete conditioning regimen using 100mg (n-96) were compared to those receiving 60mg (n-234; <100mg dose) with respect to HSCT outcomes. Alemtuzumab based T deplete conditioning regimens included Fludarabine(Flu)-Busulphan(Bu) (2 doses as reduced intensity) while Flu-Bu4 or Bu4-Cyclophosphamide used as myeloablative protocol. Standard supportive care for GVHD prophylaxis (ciclosporin), viral/bacterial and anti-fungal prophylaxis was used. Close monitoring for infections, GVHD, chimerism (included fractionated lymphoid/myeloid) and disease assessments post HSCT were undertaken as per institutional policy. The data was compared and statistically analysed using Log-rank test for overall survival (OS), Cox regression for adjusted multivariate analysis and Gray method for cumulative incidences for NRM and relapses. Results Baseline characteristics (Table-1) were similar between the 2 groups in terms of conditioning intensity, patient age, underlying disease (AML/MDS), disease risk and donor HLA matching. Median follow up of survivors was 34 months (range 01-112months) with significantly longer follow up available for 100mg dose group (median 90 months vs 28 months; p<0.001). Higher Alemtuzumab dosage (100mg) was associated with a significant improvement in GVHD & Relapse free survival (GRFS)(32% vs 20% at 12 months;p-0.003; Fig 1a) and significantly lower incidence of both grade 3-4 acute (18% vs 42% at D100;p-<0.001; Fig 1b) and chronic GVHD (all grades)(21% vs 42% at 12 months; p<0.001; Fig 1c) compared to <100mg dose. No differences in OS (66% vs 71% at 12 months; p-0.62; Fig 1d), NRM (17% vs 16% at 12 months; p-0.37; Fig 1e) and relapse incidences (24% vs 24% at 12 months;p-0.71; Fig 1f) were observed with no impact on rates of CMV/EBV reactivation, disseminated Adenoviraemia or invasive fungal disease(IFD) between the 2 cohorts. Multivariate adjusted cox analysis (MVA) confirmed older age>60 years, mismatched unrelated donor, absence of chronic GVHD, disease relapse, ITU admission event, CMV reactivation and absence of any EBV reactivation post HSCT as significant predictive factors for poor OS. This was not affected by different Alemtuzumab dosages, disease risk index or type of disease. However, GFRS was positively influenced by standard 100mg Alemtuzumab dose (HR 0.67; 95%CI: 0.51-0.86; p-0.005), no ITU admission event (HR-0.51; 95%CI:0.38-0.70; p<0.001) and EBV reactivation (HR-0.67; 95%CI:0.52-0.86; p-0.02) on multivariate analysis. NRM was worse for patients admitted in ITU, no known chronic GVHD, mismatched unrelated donor, presence of CMV and absence of EBV reactivation (p<0.001), but not affected by differential alemtuzumab dosages. Conclusions With improved supportive care, effective infection management and pre-emptive cellular therapy approaches available in current era, standard dosage (100mg) of alemtuzumab is safe and effective in both RIC and myeloablative allo-HSCTs for myeloid malignancies, with significantly lower GVHD related morbidity and overall better GFRS. Despite concerns of relapses and delayed immune reconstitution, this report on a homogenous cohort of allo-HSCTs in myeloid malignancies confirms the contrary with no impact on OS, NRM or relapses and no significant increase in opportunistic infections with 100mg dose. Disclosures Mufti: Celgene: Consultancy, Research Funding. De Lavallade:Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding.

Preparation and investigation of the ayurvedic churna formulation for diabetes

Out of most of the dreadful diseases in the world Diabetes, shortly known as DM, is the most dreadful. The primary cause of diabetes is the lack of insulin due to the insufficient secretion of insulin by the pancreas or the insensitivity of the body to reuptake the insulin. This results in the accumulation of the sugar or glucose in the blood, only thereby disturbing all the other physiological conditions in the body. Herbs, as we know, are devoid of or have very fewer side effects when compared to the antidiabetic synthetic drugs. There is evidence to show that the herbs are safer and the chemical leads that are isolated from the medicinal plants are potent in controlling diabetes. The antidiabetic activity of herbs was proven, and the mechanism of action of the drugs was also established in many pieces of research. The polyherbal churna was prepared using various herbs like Tinospora, Glycerrihiza etc. that are already proven for the antidiabetic activity. This formulation was investigated for the antidiabetic activity at two doses and was compared with a marketed formulation and also a standard synthetic drug in STZ induced DM method. The prepared churna formulation showed a better activity compared with the standard and the marketed churna. The prepared churna at 200mg dose showed better activity than the 100mg dose.

An open-label, multi-center phase I study of the safety and tolerability of the novel immunomodulatory agent PG545 in subjects with advanced solid tumors.

3083 Background: PG545 (pixatimod, pINN) is a novel immunomodulatory agent which stimulates dendritic cells (DC) via TLR9/IL-12 pathway to activate natural killer (NK) cells. It also inhibits tumour-associated macrophages in cancer models. We report on safety, PK, PD, and antitumor activity of PG545 monotherapy. Methods: In this dose escalation (3+3 design) study, eligible pts (ECOG≤1) with advanced solid malignancies who failed standard therapies received PG545 once weekly as a 1-hour i.v. infusion until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity based on RECIST (1.1) criteria, PK and PD (plasmacytoid DC & NKp46+NK cells from PBMC, and plasma cytokines/chemokines). Results: The study recruited 23 subjects across four cohorts (25, 50, 100 & 150 mg). Three dose limiting toxicities (DLTs) - hypertension (2), epistaxis (1) - occurred in the 150 mg cohort, which was identified as a non-tolerated dose level. No DLTs occurred in the 100 mg cohort, which was identified as the MTD. Six SAEs were reported to be possibly or likely related to PG545 treatment. No RECIST 1.1 objective responses were reported; best response was prolonged stable disease up to 24 weeks (mCRC), with disease control rate in evaluable subjects of 38% (6/16) at eight weeks. Exposure (AUC0-last) was proportional up to 100mg and mean half-life was 144 hours. At 50 and 100mg dose levels, two subjects in each cohort exhibited up to 4-fold increased numbers of NKp46+NK cells, IFN-α-producing pDCs, and increases (up to 25-fold) in plasma IFN-γ, TNF-α, IP-10 and MCP-1. Conclusions: PG545 is well tolerated up to 100 mg once-weekly via i.v. infusion. Human exposure data at 50mg and 100mg reach exposures consistent with those required for preclinical efficacy. Preliminary PD data support the proposed mechanism of action, which represents a promising approach to improve the efficacy of existing therapies. These data, and the absence of toxicities associated with chemo- or immunotherapies, support the development of PG545 in combination clinical trials. Clinical trial information: NCT02042781.

PHARMACOKINETICS OF BENZNIDAZOLE IN CHAGAS DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background: Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug have contributed to limited availability in several jurisdictions.Objective: To conduct systematic literature review and Bayesian meta-analysis of pharmacokinetic studies to improve estimates of basic pharmacokinetic properties of benznidazole.Methods: A systematic search of Embase, Medline, LILACS and Scielo was conducted. Eligible studies reported patient-level data from single 100mg dose pharmacokinetic evaluations of benznidazole in adults, or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. The use of secondary data (i.e. studies that did not include patient level, single 100mg dose data) was used for the generation of empiric priors for the Bayesian analysis.Results: The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated including AUC, Cmax, Tmax, elimination (Kelim) and absorption (Ka) rate constants, absorption and elimination half-life, apparent oral clearance and apparent oral volume of distribution. The results showed consistency across studies. The AUC and Cmax were 51.31mg*h/L (95% CrI: 45.01, 60.28) and 2.19mg/L (95% CrI: 2.06, 2.33), respectively. The ka and Kelim were 1.16h-1(95% CrI; 0.59, 1.76) and 0.052h-1(95% CrI; 0.045, 0.059), respectively, with corresponding absorption and elimination half-lives of 0.60h (95% CrI; 0.38, 1.11) and 13.27h (95% CrI; 11.79, 15.42). The oral clearance and volume of distribution were 2.04L/h (95%CrI 1.77, 2.32) and 39.19L (95%CrI; 36.58, 42.17), respectively.Conclusions: A Bayesian meta-analysis was used to improve estimates of the standard pharmacokinetic parameters of benznidazole. This data can inform clinicians and policymakers as access to this drug increases.

Evaluation of tolerability, safety, and pharmacokinetics of INO-1001 plus temozolomide (TMZ) in patients with unresectable stage III/IV melanoma

12015 Background: TMZ, an orally bioavailable cytotoxic agent with the same active metabolite as DTIC, is a commonly used for treatment (Rx) of metastatic melanoma (MM). It causes methylation of the O6 position of guanine. Unrepaired O6-methylguanine pairs with thymine rather than guanine and activates DNA mismatch repair. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein that functions as DNA damage sensor. PARP inhibitors increase TMZ cytotoxicity by causing interruption of the repair process of N-methylpurines generated by TMZ. INO-1001 (INO), an ultrapotent PARP inhibitor has been tested in combination of TMZ and found to be safe and well tolerated. Here we report the initial results of Phase Ib clinical trial. Methods: Patients (pts) with unresectable stage III/IV MM with no prior Rx with TMZ or DTIC were treated with INO given IV q 12 hours for 10 doses at the starting dose of 100mg/dose. The doses of INO are planned to escalate from 100 to 200mg/dose and then to the maximum dose of 400 mg/dose in successive groups of 3–6 pts. TMZ is taken po within 2 hours of the second dose of INO at the dose of 200mg/m2/day for 5 days. Blood samples are collected for pharmacokinetics study during cycle 1. The Rx cycles are repeated q 4 weeks and tumor responses are evaluated q 8 weeks. Results: 6 pts with median age 63 (range 55–67) years and median PS Zubrod 1 (range 0–2) have been treated. Initially 3 pts were treated with INO at the dose level of 100mg. One pt with a BSA of 2.76 had grade 4 neutropenia and thrombocytopenia with Rx cycle 1. TMZ dose was not adjusted to her ideal body weight. Subsequently, the dose of TMZ was reduced by 25% and the following 2 cycles were tolerated well. 3 more pts were entered at the dose level 1. To date, a total of 8 cycles of Rx have been completed. All except for the cycle mentioned earlier were tolerated well. 3 pts were evaluated for response, 1 pt had objective tumor regression, 1 had stable disease and 1 had tumor progression. The non-hematologic side effects were mild and are mostly related to TMZ. Conclusions: TMZ-INO combination is fairly well tolerated. A complete report will be presented. No significant financial relationships to disclose.

A Phase I Trial of CHIR-258, a Multitargeted RTK Inhibitor, in Acute Myeloid Leukemia (AML).

Background: CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which exhibits potent single digit nanomolar inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis (IC50 &lt;=10 for VEGFR, PDGFR, FGFR, C-KIT, and FLT-3). Approximately 30% of AML patients have a FLT-3 mutation (ITD-internal tandem duplication or catalytic domain) which drives the malignant process and confers a worse prognosis. Additionally, the inhibition of the angiogenesis component of the disease could be beneficial in all cases. Preclinical data have shown FLT3 ITD models to be ~25 fold more sensitive than FLT3 WT (Menezes, et al, Blood 2005). Our hypothesis was that AML blasts carrying FLT-3 mutations would be exquisitely sensitive to CHIR-258, but that there may also be activity against patients with wild type (wt) FLT-3. Methods: CHIR-258 was administered orally to adult patients with relapsed/refractory AML on a 7 on/7 off schedule followed by continuous daily dosing for 28 days (1 cycle). Subsequent 28-day cycles of continuous dosing were permitted. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were serially performed and drug tolerability assessed. Results: As of May 2005 8 patients have been treated in 2 (50mg and 100 mg) cohorts of 3–6 patients [median age: 62 years (range: 46–72), sex: 4M/4F, median prior relapses = 1 (range: 1–3), FAB subtypes: M1–1, M2–2, M5–1, M6–2, unclassifiable-1, no information-1] Five patients remain on study with a median number of treatment cycles=3 (range=1–11). There have been no DLTs to date. Dose escalation to 200 mg has been tolerated and accrual continues. Drug related adverse events include fatigue, anorexia, nausea/vomiting, and headache and were generally mild (CTC G1-2). Of the 8 patients treated, 1 had FLT-3 ITD mutation and 7 were wt for ITD and D835. A patient with AML-M6 with wt FLT-3 continues with stable disease after 11 cycles of therapy and was dose escalated from 50mg to 100mg after 8 cycles. The patient with FLT-3 ITD mutation treated at the 100mg dose had near complete clearing of blasts from marrow and peripheral blood. This patient later died due to a presumed fungal infection, not attributed to CHIR-258. Plasma exposure and Cmax increase proportionally across the dose range, and Cmax at the 100mg dose level is in the range where antitumor activity was seen in a preclinical oncogene addicted tumor models for FLT-3 ITD AML (MV4;11). Conclusions: CHIR-258 has demonstrated activity in relapsed refractory patients with AML, both with a FLT-3 mutation and wt FLT-3. Accrual continues at the 200mg dose cohort and updated data will be presented at the meeting.