Tolerability Of Combination Therapy Research Articles

Evaluating the Efficacy, Safety, and Tolerability of Combination Therapy of Dapagliflozin and Linagliptin Over Dapagliflozin and Vildagliptin in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin.

Background Type 2 diabetes mellitus (T2DM) patients commonly undergometformin monotherapy.This study aims to compare the efficacy, safety, and tolerability of combination therapy of dapagliflozin plus linagliptin versus dapagliflozin plus vildagliptin as add-on therapy in T2DM patients inadequately controlled on metformin. Methodology This was an 18-week, multicenter, randomized, double-blind, active-controlled, parallel-group, phase III clinical study. About 236 participants were randomly assigned to receive either a fixed-dose combination of dapagliflozin 10 mg plus linagliptin 5 mg tablets or a fixed-dose combination of dapagliflozin 10 mg plus vildagliptin SR 100 mg tablets added to metformin monotherapy. The primary outcome was the mean change in hemoglobin A1c (HbA1c) from baseline to the end of week 16. The key secondary endpoints were mean change in postprandial blood glucose (PPBG), fasting blood glucose (FBG), body weight, and the proportion of participants achieving HbA1c less than 7.0%. Results The dapagliflozin/linagliptin combination therapy showed a more significant change in HbA1c from baseline to the end of 16 weeks (mean reduction: -1.59% vs. -1.25%) compared to dapagliflozin/vildagliptin (p < 0.0001). Additionally, compared to the dapagliflozin/vildagliptin group, the dapagliflozin/linagliptin group demonstrated a significant reduction in both PPBG (mean reduction: -59.99 mg/dL vs. -55.34 mg/dL) and FPG (mean reduction: -32.91 mg/dL vs. -26.78 mg/dL). A total of 18 adverse events were reported in 17 (7.20%) participants, all of which were mild and resolved completely. There were no serious adverse events. Conclusions Compared to dapagliflozin and vildagliptin combination therapy, dapagliflozin and linagliptin fixed-dose combination provided clinically significant improvements in glycemic control. Because of its effectiveness, safety, and tolerability, the fixed-dose combination of dapagliflozin and linagliptin was a better option for treating T2DM patients who had previously only received metformin monotherapy.

Phase II study of pembrolizumab in combination with radiation with or without olaparib in localized high-risk prostate cancer.

TPS351 Background: Definitive radiation therapy (DRT) combined with androgen deprivation therapy (ADT) remains the standard of care in patients with high-risk prostate cancer (HRPC) who do not want surgery. However, up to 50% experience biochemical recurrence (BCR) within 5 years. A phase 3 NCIC group reported the 10-year biochemical recurrence free survival was 63% in ADT plus DRT vs. 27% in ADT alone. There is an urgent need for effective novel combination strategies. We hypothesize combined immune sensitizing effects of PARPi and radiation will result in significant activity of immunotherapy in men with HRPC. Methods: This is a multicenter phase II randomized study to assess biochemical response rates, safety and tolerability of combined therapy in pts with localized HRPC who elected for concurrent DRT. A total of 64 pts will be randomized 1:1 to receive either pembrolizumab (P) combined with olaparib or single agent P in addition to the standard of care ADT with DRT. Hypofractionated IMRT (2.4 to 4 Gy per fraction over 4-6 weeks) will be delivered and all pts will receive adjuvant P for one year and ADT for at least 18 months. All pts will undergo germline testing. Key eligible criteria include biopsy confirmed prostate adenocarcinoma who meets at least one of the four high-risk features: 1) clinical T3a, T3b or T4, 2) N1, 3) Gleason grade group 4 or 5, and 4) PSA &gt;20 ng/ml. Patients with less than 2 cm pelvic nodes and received ADT therapy within 3months prior to study enrollment are allowed. PSA &gt;150 ng/ml and patients with distant metastases will be excluded. The primary endpoint is to assess the proportion of patients who achieve a PSA nadir level of ≤ 0.06 ng/ml within six months after completion of radiation therapy in each arm. The secondary objectives include safety/tolerability, BCR and metastasis-free survival at 3 years. BCR is defined by the Phoenix definition. The study is designed to detect a 15% improvement in PSA nadir ≤ 0.06 ng/mL within 6 months after completion of the combined therapy versus historical control group data Geara FB et al., 2017. Enrollment began in August 2023. Clinical trial information: NCT05568550 .

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis.

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

Abstract OT3-09-01: Clinical Trial of Alpelisib and Tucatinib in Patients with PIK3CA-Mutant HER2-Positive Metastatic Breast Cancer

Abstract Phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in resistance to the drugs targeting human epidermal growth factor receptor 2 (HER2). Activating mutations in the gene encoding alpha catalytic subunit of PI3K (PIK3CA) are present in approximately 30% of HER2+ tumors. PIK3CA mutations are linked to drug resistance and decreased survival in patients with HER2+ breast cancer. To overcome this resistance mechanism, we designed a phase IB/II clinical trial to evaluate the combination of HER2 small molecule inhibitor tucatinib with PI3K inhibitor alpelisib in patients with HER2+ metastatic breast cancer (NCT05230810). This multicenter clinical trial is conducted through the Academic Breast Cancer Consortium (ABRCC), with the University of Colorado Cancer Center as the lead site. Target enrollment: 40 patients. This is a run-in phase IB/roll-over phase II study. Phase IB will follow Time-to-Event Bayesian Optimal Interval design and enroll from 9 to 19 patients to find the maximum tolerated doses (MTDs) of tucatinib and alpelisib. From 21 to 31 patients will be enrolled in phase II part, for a total of 40 patients in the final efficacy analysis. Main inclusion criteria: 1. Women and men ≥ 18 years old 2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 3. Presence of activating PIK3CA mutation in the tumor 4. Patients with HR-/HER2+ or HR+/HER2+ breast cancer may enroll; ovarian suppression is mandatory for premenopausal patients with HR+/HER2+ disease 5. HR+/HER2+ patients should be agreeable to concomitant treatment with fulvestrant 6. Prior treatment with at least two FDA-approved HER2-targeted agents 7. Measurable or evaluable disease. Bone only disease is allowed. 8. Subjects with untreated central nervous system (CNS) metastases not needing immediate local therapy, and subjects with previously treated stable or progressive brain metastases may enroll, provided that there is no indication for immediate re-treatment. For patients with treated CNS metastases: time from treatment of CNS disease until the first dose of study drugs should be as follows: WBRT ≥ 21 days, surgical resection ≥ 14 days, SRS ≥ 7 days. 9. Adequate organ and marrow function Main exclusion criteria: 1. Contraindications to undergo contrast brain MRI 2. Leptomeningeal disease 3. Poorly controlled seizures 4. Diabetes mellitus type I, or uncontrolled diabetes mellitus type II 5. Acute pancreatitis within 1 year of screening, or history of chronic pancreatitis 6. History of severe cutaneous hypersensitivity reactions 7. Toxicities of prior cancer therapies that have not resolved to grade 1 or less, except peripheral neuropathy, which must have resolved to grade 2 or less, and alopecia 8. Previous treatment with EGFR or HER2 tyrosine kinase inhibitors, or PI3K/mTOR/AKT inhibitors. 9. Systemic anti-cancer therapy, palliative radiation to extracranial sites, or surgery within 2 weeks of the first dose of study drugs 10. Active bacterial, fungal, or viral infections, hepatitis B, C, or HIV 11. Clinically significant cardio-vascular disease Primary objectives: • Phase IB: safety and tolerability of combination therapy • Phase II: efficacy by progression free survival Exploratory assessment of biomarkers will be performed in the liquid biopsy samples. Study contact: Elena Shagisultanova, MD, PhD, elena.shagisultanova@cuanschutz.edu Citation Format: Elena Shagisultanova, Kari B. Wisinski, Chelsea D. Gawryletz, Farrah M. Datko, Diana Medgyesy, Jennifer R. Diamond, Virginia F. Borges, Peter Kabos. Clinical Trial of Alpelisib and Tucatinib in Patients with PIK3CA-Mutant HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-09-01.

Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients

IntroductionCombining lenvatinib with a programmed cell death protein-1 (PD-1) inhibitor has been explored for the treatment of un-resectable hepatocellular carcinoma (uHCC). This study aimed to investigate the real-world efficacy of and prognostic factors for survival associated with lenvatinib plus PD-1 inhibitor treatment in a large cohort of Asian uHCC patients even the global LEAP-002 study failed to achieve the primary endpoints.MethodsPatients with uHCC treated with lenvatinib and PD-1 inhibitors were included. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and adverse events (AEs). Prognostic factors for survival were also analyzed.ResultsA total of 378 uHCC patients from two medical centers in China were assessed retrospectively. The median patient age was 55 years, and 86.5% of patients were male. Hepatitis B virus (HBV) infection (89.9%) was the dominant etiology of uHCC. The median OS was 17.8 (95% confidence interval (CI) 14.0–21.6) months. The median PFS was 6.9 (95% CI 6.0–7.9) months. The best ORR and disease control rate (DCR) were 19.6% and 73.5%, respectively. In multivariate analysis, Child‒Pugh grade, Barcelona Clinic Liver Cancer stage, Eastern Cooperative Oncology Group performance status score, involved organs, tumor burden score, and combination with local therapy were independent prognostic factors for OS. A total of 100% and 57.9% of patients experienced all-grade and grade 3/4 treatment-emergent AEs, respectively.ConclusionThis real-world study of lenvatinib plus PD-1 inhibitor treatment demonstrated long survival and considerable ORRs and DCRs in uHCC patients in China. The tolerability of combination therapy was acceptable but must be monitored closely.

Lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma: A large real-world study from two centers.

e16155 Background: Combining lenvatinib (a multikinase inhibitor) with programmed cell death protein-1 (PD-1) inhibitor has been explored in Unresectable hepatocellular carcinoma (uHCC) in phase 1b trials. This study aimed to investigate the real-word efficacy and safety of lenvatinib plus PD-1 inhibitor for large Chinese patients uHCC cohorts. Methods: BCLC stage B or C uHCC patients were included. Data was collected from Oct 2017 to Nov 2021 retrospectively. Patients were treated with lenvatinib and PD-1 inhibitor (pembrolizumab or nivolumab or camrelizumab or sintilimab or toripalimab or tislelizumab). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR) evaluated by RECIST v1.1 criteria. Adverse events (AEs) were assessed using CTCAE v5.0. Prognostic factors of survival were also analyzed. Results: 378 uHCC patients of BCLC stage B (12.7%) and C (87.3%) from two medical centers were included in China. The median age was 55 (range 18-89) years and 86.5% patients were male. ECOG scores were 0 (43.7%), 1 (43.4%) and 2 (13.0%), while Child-pugh grade were A (77.5%) and B (22.5%) respectively. The median OS was 17.8 (95% CI 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best objective response rate (ORR) and disease control rate (DCR) was 74/378 (19.6%) and 278/378 (73.5%) respectively. Child-pugh grade (A vs. B), ECOG score (0 vs. 1-2), BCLC stage (B vs. C) and achieve response (yes vs. no) were the prognostic factors for both OS and PFS. All (100%) experienced all-grade adverse events (AE). The most frequent AEs were fatigue, diarrhea, hypertension, decreased appetite. The most common ≥Grade 3 AEs were hypertension (13.2%), fatigue (7.1%), decreased platelet count (6.3%), increased blood bilirubin (6.1%), diarrhea (6.1%) and gastrointestinal hemorrhage (4.8%). Conclusions: This real-world study of lenvatinib plus PD-1 inhibitors achieved long survival and considerable ORR for uHCC patients in China. The tolerability of combination therapy was acceptable but should be still monitored closely. Clinical trial information: NCT03892577. [Table: see text]

Combining Antidepressants vs Antidepressant Monotherapy for Treatment of Patients With Acute Depression

Combining antidepressants is frequently done in the treatment of acute depression, but studies have yielded conflicting results. To conduct a systematic review and meta-analysis assessing efficacy and tolerability of combination therapy. Combinations using presynaptic α2-autoreceptor antagonists or bupropion were investigated separately. MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were systematically searched from each database inception through January 2020. Randomized clinical trials (RCTs) comparing combinations of antidepressants with antidepressant monotherapy in adult patients with acute depression were included. Following guidelines from Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and recommendations from the Cochrane Handbook, 2 reviewers independently performed a literature search, study selection, data extraction, and evaluation of risk of bias. Data were pooled in random-effects analyses. Primary outcome was efficacy measured as standardized mean difference (SMD); secondary outcomes were response, remission, change from baseline in rating scale scores, number of dropouts, and number of dropouts due to adverse events. Thirty-nine RCTs including 6751 patients were eligible. Combination treatment was statistically significantly associated with superior treatment outcomes relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44). Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Bupropion combinations were not superior to monotherapy (SMD = 0.10; 95% CI, -0.07 to 0.27). Numbers of dropouts and dropouts due to adverse events did not differ between treatments. Studies were heterogeneous, and there was indication of publication bias (Egger test result was positive; P = .007, df = 36), but results remained robust across prespecified secondary outcomes and sensitivity and subgroup analyses, including analyses restricted to studies with low risk of bias. In this meta-analysis of RCTs comparing combinations of antidepressants with antidepressant monotherapy, combining antidepressants was associated with superior treatment outcomes but not with more patients dropping out of treatment. Combinations using an antagonist of presynaptic α2-autoreceptors may be preferable and may be applied as a first-line treatment in severe cases of depression and for patients considered nonresponders.

Safety and tolerability of combination therapy with ambrisentan and tadalafil for the treatment of pulmonary arterial hypertension in children: Real-world experience.

To describe the safety and tolerability of treatment with ambrisentan and tadalafil in pediatric pulmonary hypertension (PH). This retrospective observational two-center study included subjects (≤18 years of age) with PH receiving combination therapy with ambrisentan and tadalafil. Before initiating this therapy, many patients were on other therapies for PH. At baseline, patients either received no therapy or monotherapy with a phosphodiesterase 5 inhibitor (PDE5i) or endothelin receptor antagonist (ERA) (Group A), switched from a different PDE5i and ERA (Group B), or were on prostanoid therapy with or without a PDE5i and/or ERA (Group C and D). Demographics, symptoms, and adverse effects were collected. Pre- and postvalues for exercise capacity, hemodynamics, and biomarkers were compared. There were 43 subjects (26 F, 17 M) ages 4-17.5 years (median 9.3) with World Symposium of PH group 1, 3, and 5. Significant improvements were seen in change scores at follow-up in the entire sample and Group A for 6-min walk distance: +37.0 (6.5-71.0) [p = 0.022], mean pulmonary artery pressure: -6.0 (-14.0 to -3.5) [p = .002], pulmonary vascular resistance: -1.7 (-6.2 to -1.0) [p = .003], NT-proBNP -32.9 (-148.9 to -6.7) [p = .025]. WHO functional class improved in 39.5% and was unchanged in 53.5%; PHrisk scores improved in 16%; were unchanged in 56%; and declined in 14%. Three patients discontinued therapy (two headaches, one peripheral edema). Seven patients were hospitalized for worsening disease (2/7 had a Potts shunt placed, 2/7 had an atrial septostomy). There were no deaths or lung transplantation. Combination therapy with ambrisentan and tadalafil was well-tolerated, with an acceptable safety profile in a select group of children. This therapy was associated with improved exercise capacity and hemodynamics in children who were treatment naïve or on monotherapy with a PH medication before the initiation of ambrisentan and tadalafil. Based on these early data, further study of combination therapy in pediatric PH is warranted.

The effectiveness of nifedipine/indomethacin combination therapy and nifedipine monotherapy for postponing preterm birth (25\u201334\u2009weeks of gestation) in Sudanese women: a randomized clinical trial study protocol

BackgroundPreterm birth is the most common cause of neonatal morbidity and mortality. Tocolytics are considered a standard treatment for women with threatened preterm delivery to allow time for maternal steroid administration and transfer to referral centers with neonatal intensive care units. However, there is controversy about the best tocolytic therapy to be considered as the first choice. The aim of this study is to compare the tocolytic effectiveness and tolerability of combination therapy with nifedipine and indomethacin versus nifedipine monotherapy among Sudanese women with preterm labor (PTL) as well as to compare the possible neonatal outcomes associated with each drug.Methods/designThis is a randomized controlled clinical trial to be conducted in the Medani Maternity Hospital, Sudan. Women aged 18–40 years that are diagnosed with preterm labor and have a gestational age between 25 and 34 weeks will be eligible to participate in this trial. The diagnosis of threatened PTL is defined as persistent uterine contractions “(four contractions every 20 min or eight contractions every 60 min)” with cervical changes “(cervical effacement ≤80% or cervical dilatation >two cm)”. Patients will be eligible regardless of the presentation of the fetus. It will be randomly decided whether participants receive nifedipine/indomethacin combination therapy or nifedipine monotherapy. The primary outcome is the number of women who do not deliver and do not need alternative tocolytic drug (terbutaline). The secondary outcome is an estimated association with neonatal morbidity and mortality. The sample size will be 117 subjects in each arm of the study, according to a type I error of 0.05 and a study power of 80%.DiscussionWe expect higher effectiveness of the combination indomethacin/nifedipine tocolytic therapy compared with nifedipine monotherapy. We plan to suggest this combination therapy as the best option for postponing PTL.Trial registrationClinical trial registration: PACTR202004681537890, date of registration: March 8, 2020.

Safety and tolerability of combination therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A multicenter retrospective observational study in Japan.

Phase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited. The retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records. Nintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender-Age-Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax). Real-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile.

Efficacy and tolerability of combination therapy with alpha-blockers and phosphodiesterase-5 inhibitors compared with monotherapy for lower urinary tract symptoms: Protocol for a systematic review and network meta-analysis.

Purpose:This study aimed to compare the efficacy and safety of combination therapy consisting of α-blockers and different phosphodiesterase type 5 inhibitors for lower urinary tract symptoms (LUTS) by performing a network meta-analysis.Method:Relevant articles were retrieved from the Cochrane Library, PubMed, and EMBASE databases. Bayesian network meta-analyses were performed with a random-effect model to compare the efficacy and safety of combination therapy with α-blockers and phosphodiesterase-5 inhibitors for LUTS. The odds ratio (OR), mean difference (MD) and surface under the cumulative ranking curve (SUCRA) were calculated with the GeMTC R package.Results:Twenty randomized trials with 4131 patients were included in this network meta-analysis. Based on the SUCRA values, vardenafil (10 mg) combined with α-blockers ranked first, first and sixth; sildenafil (25 mg) combined with α-blockers ranked second, third and first; and tadalafil (20 mg) combined with α-blockers ranked third, second and fourth in IPSS, post void residual, and maximum flow rate, respectively.Conclusions:Combination therapy with α-blockers and phosphodiesterase-5 inhibitors was effective and well tolerated for LUTS. For men who prioritize high efficacy, vardenafil (10 mg) combined with α-blockers seems to be the treatment of choice. For men wishing to optimize minimally invasive treatment, sildenafil (25 mg) and tadalafil (20 mg) combined with α-blockers appears to have a possible advantage in terms of avoiding adverse effects.

Pirfenidone plus inhaled N-acetylcysteine for idiopathic pulmonary fibrosis: a randomised trial.

A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown. This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (D LCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability. 81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in D LCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups. Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.

Molecular surveillance of the Pfmdr1 N86Y allele among Congolese pregnant women with asymptomatic malaria

BackgroundMalaria in pregnancy is associated with considerable morbidity and mortality. Regular surveillance of artemisinin-based combination therapy tolerance, or molecular makers of resistance, is vital for effective malaria treatment, control and eradication programmes. Plasmodium falciparum multiple drug resistance-1 gene (Pfmdr1) N86Y mutation is associated with reduced susceptibility to lumefantrine. This study assessed the prevalence of Pfmdr1 N86Y in Brazzaville, Republic of Congo.MethodsA total 1001 of P. falciparum-infected blood samples obtained from asymptomatic malaria pregnant women having a normal child delivery at the Madibou Integrated Health Centre were analysed. Pfmdr1 N86Y genotyping was conducted using PCR-restriction fragment length polymorphism.ResultsThe wild type Pfmdr1 N86 allele was predominant (> 68%) in this study, whereas a few isolates carrying the either the mutant allele (Pfmdr1 86Y) alone or both alleles (mixed genotype). The dominance of the wildtype allele (pfmdr1 N86) indicates the plausible decline P. falciparum susceptibility to lumefantrine.ConclusionThis study gives an update on the prevalence of Pfmdr1 N86Y alleles in Brazzaville, Republic of Congo. It also raises concern on the imminent emergence of resistance against artemether–lumefantrine in this setting. This study underscores the importance to regular artemether–lumefantrine efficacy monitoring to inform the malaria control programme of the Republic of Congo.

Chondroprotector transdermal magnetophoresis for osteoarthritis of the knee

Treatment of osteoarthritis (OA) is a relevant problem of rheumatology. Despite a significant number of medical approaches and the creation of new drugs, the effectiveness of treatment remains unsatisfactory, which necessitates the creation of complex treatment programs. Pulse low-frequency magnetotherapy is a modern method that makes it possible to potentiate the therapeutic effects of chondroprotectors for transdermal administration using magnetophoresis technology. To evaluate the efficacy and tolerability of combination therapy using chondroprotective magnetophoresis using 'running' pulsed magnetic field (RPMF) and application of chondroxide (transdermal gel form) in patients with knee OA. A randomized, placebo-controlled clinical trial included 65 patients with grade II - III knee OA according to the Kellgren-Lwrence classification. The 1st group included 25 patients who received local therapy - chondroxide magnetophoresis using RPMF (20 mT, frequency 6.25 Hz, exposure time 20 min, No. 12); in the 2nd group - 20 patients who underwent placebo-magnetotherapy of chondroxide; in the 3rd group - 20 patients who used RPMF without local chondroprotective therapy. We used VAS, WOMAC scales, EQ-5D questionnaire, OMERACT-OARSI criterion in order to analyze the results. A pronounced analgesic effect of the treatment was registered (according to the VAS and WOMAC scales) in patients receiving magnetotherapy (p<0.01). A significant improvement in functional parameters (according to WOMAC) was noted, more pronounced in patients who used chondroxide magnetophoresis (p<0.001). During the course of treatment, a positive effect of magnetotherapy on the indicators of quality of life (according to EQ-5D) was registered. A high percentage of response (68.1%) to therapy using magnetophoresis of the transdermal form of chondroxide (according to OMERACT-OARSI) was demonstrated. No adverse reactions were registered during treatment. The use of the local therapy method in the form of magnetophoresis of the transdermal form of the chondroxide is an effective and safe treatment technology that improves the functional state and quality of life of patients with OA of the knee joint.

A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial

BackgroundNonalcoholic steatohepatitis (NASH) is a multifactorial disease involving different contributing mechanisms, with no approved therapies so far. Tropifexor (TXR), a farnesoid X receptor agonist, and cenicriviroc (CVC), a chemokine receptor types 2/5 antagonist, target the steatotic, inflammatory, and/or fibrotic pathways involved in NASH. DesignTANDEM (CLJC242A2201J; NCT03517540) is a 48-week, phase 2b, randomized, double-blind, multicenter study in 200 adult patients with biopsy-proven NASH and liver fibrosis. Patients will be randomized in a 1:1:1:1 ratio to receive either TXR 140 μg once daily (qd), CVC 150 mg qd, TXR 140 μg + CVC 150 mg qd, or TXR 90 μg + CVC 150 mg qd. The study comprises a 48-week treatment period and 4 weeks of follow-up. The key inclusion criterion is presence of NASH with fibrosis stage F2/F3 as seen on screening liver biopsy or on historical liver biopsy performed within 6 months prior to screening. ObjectivesThe primary objective is evaluation of the safety and tolerability of combination therapy compared with the monotherapies over 48 weeks. The secondary objective is to evaluate efficacy as assessed by ≥1-point improvement in liver fibrosis versus baseline or resolution of steatohepatitis after 48 weeks. SummaryTANDEM will evaluate the combination of TXR and CVC with respect to safety and efficacy outcomes related to improvement in fibrosis or resolution of steatohepatitis. Given the effects of TXR and CVC in multiple pathophysiological pathways associated with NASH, combination therapy is likely to show additional benefits compared with monotherapy.

Efficacy and Safety of a Fixed-Dose Combination of Candesartan and Rosuvastatin on Blood Pressure and Cholesterol in Patients With Hypertension and Hypercholesterolemia: A Multicenter, Randomized, Double-Blind, Parallel Phase III Clinical Study

PurposeThe aim of this study was to evaluate the blood pressure–lowering and cholesterol-lowering effects of a fixed-dose combination therapy using candesartan (CND)/rosuvastatin (RSV) compared with CND or RSV monotherapy in patients with hypertension and hypercholesterolemia. MethodsThis study was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 394 patients were screened. After a 4-week run-in period, 219 of these patients with hypertension and primary hypercholesterolemia were randomized. Patients received 1 of 3 regimens for 8 weeks: (1) CND 32 mg/RSV 20 mg, (2) RSV 20 mg, or (3) CND 32 mg. The primary outcome variables were changes in the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the percentage changes in LDL-C from baseline to the drug treatment at 8 weeks. The secondary outcome variables were percentage changes of total cholesterol, triglycerides, HDL-C, non–HDL-C, apolipoprotein B, apolipoprotein A-I, high-sensitivity C-reactive protein, and glucose metabolic indices, including percentage changes of the homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and hemoglobin A1c. Tolerability of combination therapy was compared with other monotherapy groups. FindingsThe percentage changes of LDL-C were −48.6% (from 157.2 to 80.1 mg/dL) in the RSV group and −49.8% (from 160.2 to 78.9 mg/dL) in the CND/RSV group from baseline to the end of 8 weeks of treatment. Mean SBP and DBP were significantly decreased in the CND/RSV and CND groups after 8 weeks (P < 0.001 for all); however, no significant differences were found between the 2 groups. Total cholesterol levels, triglycerides, non–HDL-C, and apolipoprotein B were significantly reduced in the CND/RSV and RSV groups, with no significant differences between the groups compared with the CND group (P < 0.001 for all). The percentage changes of HOMA-IR, adiponectin, and hemoglobin A1c had no significant differences between the combination groups and monotherapy groups. However, in a 2-sample t test, HOMA-IR was significantly decreased in the CND/RSV group compared with the RSV group in nondiabetic patients (mean [SD] percentage change of HOMA-IR, −8.7% [37.6%] vs 17.1% [53.1%]; P = 0.048). There were no significant differences in metabolic indices between the diabetic groups. Adverse events in the CND/RSV group were similar to those in the monotherapy group. ImplicationsOnce-daily fixed-dose combination therapy with CND/RSV is an effective, tolerable, convenient treatment option for patients with essential hypertension and hypercholesteremia. ClinicalTrials.gov identifier: NCT02770261.

PB2203 IMPROVEMENT OF THE HEMATOLOGIC TOXICITIES OF RUXOLITINIB IN PATIENTS WITH MPN‐ASSOCIATED MYELOFIBROSIS USING A COMBINATION OF THALIDOMIDE, STANOZOLOL AND PREDNISONE

Background:Anemia and thrombocytopenia are the most frequently reported adverse events of ruxolitinib in patients with MPN‐associated myelofibrosis (MPN‐MF). Although thalidomide, androgens and prednisone have previously demonstrated improvements in myelofibrosis‐associated anemia, it is unclear whether these drugs are effective in patients taking ruxolitinib.Aims:To evaluate the efficacy and tolerability of combination therapy with low dose thalidomide, stanozolol and prednisone (TSP) in patients with IPSS intermediate‐2 or high‐risk myelofibrosis (MF) who received ruxolitinib treatment.Methods:Sixty‐five patients with MPN‐MF who took ruxolitinib were enrolled in this retrospective study, of which 46 patients also took TSP while 19 did not take TSP (TSP and non‐TSP groups).Results:Within the first 24 weeks, the proportion of patients with anemia and platelet count ≥50 × 109/L were 45.7% and 67.4% in the TSP group as compared to 0% and 10.5% in the non‐TSP group (p &lt; 0.001). The mean hemoglobin level in the non‐TSP group reached the nadir after approximately 12–16 weeks of therapy, but gradually increased in the TSP group.Summary/Conclusion:In summary, TSP regime can improve anemia and thrombocytopenia during ruxolitinib treatment in patients with MPN‐MF, and the associated adverse events were manageable.image

The IRX-2 regimen combined with nivolumab in recurrent/metastatic solid tumors: A phase 1b study to evaluate the safety, determine recommended phase 2 dose (RP2D), and investigate the biologic and clinical activity.

TPS2662 Background: IRX-2 is a biologic immunotherapeutic containing a mixture of cytokines including IL-2, IL-1β IL-6, IL-8, TNFα, GM-CSF, and IFN-γ. It is derived from stimulating human PBMCs with phytohemagglutinin. Preclinical studies have shown that IRX-2 enhances dendritic cell maturation, T cell activation, and NK cell stimulation. In a Phase 2 trial of head and neck squamous cell carcinoma (HNSCC) patients, IRX-2 increased immune activation in the tumor microenvironment and was correlated with greater progression free survival and overall survival. Moreover, it has been shown that the degree of lymphocyte infiltration is an important prognostic factor for treatment with anti- programmed cell death protein 1 (PD-1) monoclonal antibodies. These data provide a compelling rationale for incorporating IRX-2 regimen into anti-PD-1 treatment strategies to increase the level of lymphocyte infiltration in the TME and improve immune response. Methods: This is a phase Ib trial exploring safety and tolerability of IRX-2 regimen in combination with nivolumab. Patients with recurrent or metastatic renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, HNSCC and melanoma are eligible. Patients who have received prior anti-PD-1/PD-L1 antibodies are eligible. IRX-2 regimen consists of cyclophosphamide 300mg/m2 (Day 1) and subcutaneous IRX-2 injections in 2 or 4 lymph node-bearing regions (based on dose level) for 10 days every 3 months. Two dose levels of IRX-2 regimen will be studied. Nivolumab is administered at 240 mg Q2W. Once the RP2D is determined, an additional 88 pts will be enrolled in an expansion phase, for a planned total enrollment of approximately 100 pts. Dose expansion phase will include cohorts of the 5 different diseases. Each cohort will include two groups: 1) anti-PD-1/PD-L1 antibody naïve tumors, and 2) progressed during or after anti-PD-1/PD-L1 antibodies. The primary study objective is to determine safety and tolerability of combination therapy. Secondary objectives are to evaluate the objective response rate, progression-free survival, and overall survival. Study Progress: Study is actively accruing. Clinical trial information: NCT03758781.

Abstract OT1-01-03: The WinPro study: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer

Abstract Background There is bidirectional interplay between PR and ER in human breast cancers (Lim et al, Endo Rel Can 2016). There is evidence for a reprogramming of ER chromatin binding sites with 470 genes differentially regulated by dual treatment with estrogen plus progestogen compared to estrogen alone in breast cancer cell lines (Mohammed et al, Nature 2015). Functionally, there was an additive anti-cancer effect with the addition of natural progesterone to endocrine therapy in preclinical breast cancer models. Trial Design This is a phase II multi-site, randomised, open-label, three-arm, study in 200 postmenopausal women with early-stage ER+, PR+, HER2-negative breast cancer. Eligible patients will be randomised 1:1:1 to receive 14 days of intervention with either letrozole 2.5mg PO daily (arm 1), letrozole 2.5mg + prometrium 300mg PO daily (arm 2) or tamoxifen 20mg + prometrium 300mg PO daily (arm 3), between diagnosis of breast cancer and definite surgery. Australian Clinical Trials Registry: ACTRN1261800092813 Eligibility Criteria Inclusion Criteria a) Histologically confirmed ER+ and PR+ breast cancers (≥10% positive staining cells) b) HER2/CEP17 ratio of &amp;lt;2 and mean HER2 copy number &amp;lt;6 (ASCO CAP 2013 guidelines) c) Tumour size ≥1cm on ultrasound and/or mammogram d) Aged ≥18 years Exclusion Criteria a) Currently on hormone therapies (HRT and OCP) b) Locally advanced/inoperable and inflammatory breast cancer c) Clinical evidence of metastatic disease d) Received other preoperative systemic therapies e) Nut allergy (prometrium contains peanut oil) f) Prior history of uterine cancer, deep vein thrombosis, pulmonary embolism or clotting disorder g) Women who are pregnant/breast feeding Specific Aims a) Primary Endpoint The geometric mean suppression of the centrally assessed proliferation marker Ki67, after two weeks of intervention, compared with baseline. This will be obtained by comparing the mean difference in Ki67 staining between pre and post-treated samples in each intervention arm. b) Secondary Endpoint Safety and tolerability of combination therapy (NCI-CTCAE v4.0) c) Translational Endpoints 1. Define a gene set as a predictive biomarker for a reduction in Ki67 2. Evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumors following intervention 3. Evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumors following intervention Statistical Methods The IMPACT study reported a geometric mean reduction in Ki67 after 2 weeks of preoperative tamoxifen of 59.5% and anastrazole of 76% (Dowsett et al, JNCI 2007). This allows estimation of power to detect differences between Arm 1 and either Arm 2 or Arm 3 with a p-value of 0.025. For the third possible comparison of Arm 2 vs Arm 3, there is no prior evidence, therefore this as a purely exploratory comparison. With a total trial recruitment of 200 and allowing 4% dropouts, this would give 80% power to detect an improvement in Ki67 suppression from 76% in the letrozole alone control arm to 92% in either experimental arm. Accrual Present: 5 (1 site open) Target: 200 (8 sites total) Contact Information Elgene Lim, MBBS, FRACP, PhD. e.lim@garvan.com.au Citation Format: Carson E, Segara D, Parker A, O'Toole S, Coates A, Mann B, Lindeman G, Tilley W, Lim E. The WinPro study: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-03.

Improvement of the hematologic toxicities of ruxolitinib in patients with MPN-associated myelofibrosis using a combination of thalidomide, stanozolol and prednisone

ABSTRACTObjective: Anemia and thrombocytopenia are the most frequently reported adverse events of ruxolitinib in patients with MPN-associated myelofibrosis (MPN-MF). Although thalidomide, androgens and prednisone have previously demonstrated improvements in myelofibrosis-associated anemia, it is unclear whether these drugs are effective in patients taking ruxolitinib.Method: We conducted a retrospective cohort study to evaluate the efficacy and tolerability of combination therapy with low dose thalidomide, stanozolol and prednisone (TSP) in patients with IPSS intermediate-2 or high-risk myelofibrosis (MF) who received ruxolitinib treatment.Results: Sixty-five patients with MPN-MF who took ruxolitinib were enrolled in this retrospective study, of which 46 patients also took TSP while 19 did not take TSP (TSP and non-TSP groups). Within the first 24 weeks, the proportion of patients with anemia response and platelet count increase ≥50 × 109/L were 45.7% and 67.4% in the TSP group as compared to 0% and 10.5% in the non-TSP group (p < 0.001). The mean hemoglobin level in the non-TSP group reached the nadir after approximately 12–16 weeks of therapy, but gradually increased in the TSP group.Conclusion: In summary, TSP regimen can improve anemia and thrombocytopenia during ruxolitinib treatment in patients with MPN-MF, and the associated adverse events were manageable.