Dose Modification Research Articles

Evaluation of the Protective Effect of Cystone against Cisplatin Induced Nephrotoxicity in Cancer Patients

Abstract Purpose Cisplatin is a cost effective widely used antineoplastic drug to treat a number of solid tumors. The major dose-limiting toxicity is nephrotoxicity. Cystone is one of drugs that have been tested to reduce the incidence of cisplatin-induced acute kidney injury (CIAKI). This study aimed to investigate the protective effect of Cystone against CIAKI in larger number of patients relative to previously conducted pilot studies . Methods A prospective phase II, open-label randomized controlled study was conducted in patients receiving cisplatin-based chemotherapy in Ain Shams University Hospitals, using cystone tablet (manufactured by the Himalayan Pharmaceutical Company, India) administered as two pills every 8 hours continuously through course of chemotherapy starting from the day before receiving chemotherapy. A total of 99 patients were randomized between the control and cystone arms. The primary endpoint was the incidence of AKI according to Common Terminology Criteria Adverse Events (CTCAE) in each treatment arm. Secondary endpoints include need to dose modification between both arms. Results There was clinical difference in the incidence of CIAKI any grade between the two arms (12% in cystone arm vs 34 % in control arm P = 0.4. Need to dose modification is 10.4% vs 12 % (P = 0.8). There was a statistically significant difference between the two arms as regards the difference between values (mean) of serum creatinine and creatinine clearance values initially and at the end of treatment favoring drop of renal functions in control group (P = 0.000 and 0.003) respectively. Conclusion Our study did not demonstrate clearly a protective role of cystone in decreasing the incidence of CIAKI in patients receiving cisplatin based chemotherapy. However, drop of renal function in control arm with comparison to study arm may give an indication to further study cystone in different doses to assess its protective role against CIAKI.

Age Is a Risk Factor for Olaparib Dose Modification and Discontinuation in Patients With Ovarian Cancer.

Olaparib, a poly (ADP-ribose) polymerase inhibitor, is widely used as maintenance therapy for ovarian cancer. Dose modification, such as dose reduction and treatment interruption, are frequently performed to manage adverse events (AEs) of olaparib. By identifying patients at high risk for dose modification before administration, interventions related to appropriate control of AEs can be implemented. This study aimed to evaluate risk factors of olaparib dose modification and its clinical usefulness. Sixty patients with ovarian cancer who received olaparib were included in this retrospective cohort study. Associations between patients' characteristics and dose modification were evaluated by multivariate logistic regression analysis. We also examined whether risk factors of dose modification were associated with treatment discontinuation due to AEs. Twenty-five (41.7%) patients required dose modification. Patients who required dose modification were significantly older (p=0.018) and tended to be more underweight (p=0.078) than those who did not require dose modification. In multivariate analysis, increasing age was significantly associated with dose modification (odds ratio=1.056; 95% confidence interval=1.002-1.112; p=0.034). The optimal cutoff of age as a risk factor for dose modification, calculated from receiver operating characteristic curves, was 65.0 years. Patients aged 65.0 years and older were significantly more likely to discontinue olaparib owing to AEs (p=0.0437). Age is a risk factor of olaparib dose modification due to AEs. Older patients, who frequently require dose modification, are more likely to discontinue olaparib, suggesting that strict management of AEs is particularly necessary in this patient group.

Effets indésirables de l’association tezacaftor/ivacaftor/elexacaftor pouvant mener à un arrêt de traitement : à propos d’une série de 10 cas

Cystic fibrosis transmembrane regulator (CFTR) channel modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) represent a major advance in the management of cystic fibrosis. However, few data are available on the real-life safety profile of these medications, in particular on adverse events that may lead to their discontinuation. The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France). A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France. Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case. This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of "caftors", their possible risk factors, and the impact of adjusting dosing modalities.

Multicenter Analysis of Valganciclovir Prophylaxis in Pediatric Solid Organ Transplant Recipients.

Valganciclovir is the only approved antiviral for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation (SOT). Additional approaches may be needed to improve outcomes. A multicenter retrospective study from 2016 to 2019 was conducted of pediatric SOT recipients in whom at least 3 months of valganciclovir prophylaxis was planned. Episodes of CMV DNA in blood (DNAemia), CMV disease, drug-related toxicities, as well as other infections in the first year posttransplant and demographic and clinical data were collected. CMV DNAemia in the first year after prophylaxis or during prophylaxis (breakthrough) was analyzed by multivariate hazard models. Among the 749 patients enrolled, 131 (17.5%) had CMV DNAemia at any time in the first year; 85 (11.4%) had breakthrough DNAemia, and 46 (6.1%) had DNAemia after prophylaxis. CMV disease occurred in 30 (4%). In a multivariate model, liver transplantation compared to kidney or heart, intermediate or high risk based on donor/recipient serologies, neutropenia, and valganciclovir dose modifications attributed to toxicity were associated with increased risk of total and/or breakthrough DNAemia. Bacteremia was also associated with increased hazard ratio for CMV DNAemia. In a separate multivariate analysis, rejection occurred more often in those with breakthrough CMV DNAemia (P = .002); liver transplants, specifically, had increased rejection if CMV DNAemia occurred in the first year (P = .004). These associations may be bidirectional as rejection may contribute to infection risk. CMV DNAemia in the first year posttransplantation occurs despite valganciclovir prophylaxis and is associated with medication toxicity, bacteremia, and rejection. Pediatric studies of newer antivirals, especially in higher-risk subpopulations, appear to be warranted.

What Is Ailing Oncology Clinical Trials? Can We Fix Them?

Evidence from phase three clinical trials helps shape clinical practice. However, a very small minority of patients with cancer participate in clinical trials and many trials are not completed on time due to slow accrual. Issues with restrictive eligibility criteria can severely limit the patients who can access trials, without any convincing evidence that these restrictions impact patient safety. Similarly, regulatory, organizational, and institutional hurdles can delay trial activation, ultimately making some studies irrelevant. Additional issues during trial conduct (e.g., mandatory in-person visits, central confirmation of standard biomarkers, and inflexible drug dosage modification) contribute to making trials non-patient-centric. These real-life observations from experienced clinical trialists can seem nonsensical to investigators and patients alike, who are trying to bring effective drugs to patients with cancer. In this review, we delve into these issues in detail, and discuss potential solutions to make clinical trials more accessible to patients.

Biological-equivalent-dose-based integrated optimization framework for fast-energy-switching Bragg peak FLASH-RT using single-beam-per-fraction.

When comparing the delivery of all beams per fraction (ABPF) to single beam per fraction (SBPF), it is observed that SBPF not only helps meet the FLASH dose threshold but also mitigates the uncertainty with beam switching in the FLASH effect. However, SBPF might lead to a higher biological equivalent dose in 2Gy (EQD2) for normal tissues. This study aims to develop an EQD2-based integrated optimization framework (EQD2-IOF), encompassing robust dose, delivery efficiency, and beam orientation optimization (BOO) for Bragg peak FLASH plans using the SBPF treatment schedule. The EQD2-IOF aims to enhance both dose sparing and the FLASH effect. A superconducting gantry was employed for fast energy switching within 27ms, while universal range shifters were utilized to improve beam current in the implementation of FLASH plans with five Bragg peak beams. To enhance dose delivery efficiency while maintaining plan quality, a simultaneous dose and spot map optimization (SDSMO) algorithm for single field optimization was incorporated into a Bayesian optimization-based auto-planning algorithm. Subsequently, a BOO algorithm based on Tabu search was developed to select beam angle combinations (BACs) for 10 lung cases. To simultaneously consider dose sparing and FLASH effect, a quantitative model based on dose-dependent dose modification factor (DMF) was used to calculate FLASH-enhanced dose distribution. The EQD2-IOF plan was compared to the plan optimized without SDSMO using BAC selected by a medical physicist (Manual plan) in the SBPF treatment schedule. Meanwhile, the mean EQD2 in the normal tissue was evaluated for the EQD2-IOF plan in both SBPF and ABPF treatment schedules. No significant difference was found in D2% and D98% of the target between EQD2-IOF plans and Manual Plans. When using a minimum DMF of 0.67 and a dose threshold of 4Gy, EQD2-IOF plans showed a significant reduction in FLASH-enhanced EQD2mean of the ipsilateral lung and normal tissue by 10.5% and 11.5%, respectively, compared to Manual plans. For normal tissues that received a dose greater than 70% of the prescription dose, using a minimum DMF of 0.7 for FLASH sparing compensated for the increase in EQD2mean resulting from replacing ABPF with SBPF schedules. The EQD2-IOF can automatically optimize SBPF FLASH-RT plans to achieve optimal sparing of normal tissues. With an energy switching time of 27ms, the loss of fractionate repairing using SBPF schedules in high-dose regions can be compensated for by the FLASH effect. However, when an energy switching time of 500ms is utilized, the SBPF schedule needs careful consideration, as the FLASH effect diminishes with longer irradiation time.

MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331

Abstract BACKGROUND Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival. METHODS We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (>75% or <75% of planned dose) for each agent. RESULTS 274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received <75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup. CONCLUSIONS Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.

Early dose reduction of dasatinib does not compromise clinical outcomes in patients with chronic myeloid leukemia: A comparative analysis of two prospective trials

Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used as a first-line treatment option for patients with chronic myeloid leukemia (CML). Currently, dose modification due to adverse events (AEs) is common in patients treated with dasatinib. This study compared the outcomes of two sequential prospective trials that enrolled patients with newly diagnosed chronic phase of CML (CP-CML) and initiated dasatinib at a starting dose of 100 mg daily. In the PCR-DEPTH study, CP-CML patients who started dasatinib 100 mg daily were enrolled and followed up, while in the DAS-CHANGE study, when patients achieved early molecular response with any grade of AEs were enrolled and treated with dasatinib 80 mg once daily. A total of 102 patients (PCR-DEPTH) and 90 patients (DAS-CHANGE) were compared. Although the median value of the relative dose intensity (RDI) of dasatinib was significantly higher in PCR-DEPTH than in DAS-CHANGE (99.6 % vs. 80.1 %, p <0.001), the MMR rate at 12months showed a trend toward superiority in DAS-CHANGE compared to PCR-DEPTH (77.1 % vs 65.2 %, p = 0.084). The frequencies of MR4.0 at 24 and 36 months were higher in DAS-CHANGE than in PCR-DEPTH (44.4 % vs 28.8 %, p = 0.052 and 63.6 % vs 40.3 %, p= 0.013, respectively). RDIs were not different according to the MMR, MR4.0 or MR4.5 in analyses using a pooled population. Our results suggest that early dose reduction of dasatinib does not compromise efficacy in patients achieving EMR at 3 months and could be an interventional strategy for improving long term outcomes.

Issues pertaining to posology in ancient Greek, Roman and Byzantine medical texts

Researching medical texts of the past reveals that the preparation of a therapeutic recipe usually involved the use of several active ingredients. There are many detailed reports on the ratio of the ingredients in a recipe, but also on the dosage administered to the patient. In this article, we recorded the use of units of weight and volume in therapeutic recipes from antiquity, the Hellenistic era, the Roman Empire, Byzantium, and also empirical medical texts of the 19th century. The changes emerging over time from the growing trade in the wider Mediterranean area, with the introduction of both new products and new units of measurement, did not affect the basic principles of the therapeutic methods. Through the centuries, the main concern of physicians was to fight the disease without burdening the patient with any unwanted effects. In this context, we observe even dosage modifications when it comes to special vulnerable population groups, such as children, the elderly and pregnant women. The period covered is very large, which means that the approach is impressionistic not aiming to the philologists. We hope that this does not pose a problem to the interested historians of medicine.

The Effect of COVID-19 on Cardiovascular Diseases and the Need for Beta-Blocker Dose Modification

The Effect of COVID-19 on Cardiovascular Diseases and the Need for Beta-Blocker Dose Modification

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients

ObjectivesDespite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib...

Triazole antifungal drug interactions-practical considerations for excellent prescribing.

Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently prescribed antifungals but require attention to dosing and drug interactions. Nearly 600 severe drug-drug interactions and over 1100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents (see https://www.aspergillus.org.uk/antifungal-drug-interactions/). In this article, we address the common and less common, but serious, drug interactions observed in clinical practice with triazole antifungals, including a group of drugs that cannot be prescribed with all or most triazole antifungals (ivabradine, ranolazine, eplerenone, fentanyl, apomorphine, quetiapine, bedaquiline, rifampicin, rifabutin, sirolimus, phenytoin and carbamazepine). We highlight interactions with drugs used in children and new agents introduced for the treatment of haematological malignancies or graft versus host disease (midostaurin, ibrutinib, ruxolitinib and venetoclax). We also summarize the multiple interactions between oral and inhaled corticosteroids and triazole antifungals, and the strategies needed to optimize the therapeutic benefits of triazole antifungal therapy while minimizing potential harm to patients.

Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma

BackgroundTriplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse.MethodsIn this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed.ResultsA total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group.ConclusionsAmong lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-004354-21.)

Adherence for members taking oral oncolytic agents undergoing dose modification strategies.

e23058 Background: The use of oral oncolytic agents has transformed oncology care. Previous studies have reported that patient, treatment, and health system-related factors may influence adherence rates in patients prescribed oral oncolytic agents. The purpose of this study is to assess adherence rates in members of a large national pharmacy benefit manager taking oral oncolytic agents who experienced a modification to their dosing regimen. Methods: Adult members receiving palbociclib, abemaciclib, ribociclib, axitinib, lenvatinib, or cabozantinib between 01/01/2021 and 12/31/2022 were eligible for the study. Members who did not maintain continuous eligibility for 180 days prior to and 2 years after the first fill in the study period were excluded. Members were stratified by presence of dose modification, defined by a change in daily dose from one prescription to the next. Adherence was assessed via the proportion of days covered (PDC) which is the total days with medication coverage divided by the number of days between the index fill and exhaust of the final fill in the study period. Optimal adherence was defined as PDC ≥ 0.85. Standard statistical tests for continuous and categorical variables were utilized. Logistic regression was performed with the endpoint of optimal adherence. P values &lt; 0.05 are significant. Results: 13,641 members were included in the final analysis, with 7,093 (52%) experiencing a modification to their dosing regimen during the study period. Several significant differences in sociodemographic variables were present in this study with members experiencing a dose modification being older (mean [standard deviation (SD)]: 65.7 [11.9] vs. 64.9 [13.0] yr; p &lt; 0.001), more likely to be male (23.3% vs. 15.0%; p &lt; 0.001), more likely to reside in high socioeconomic status (SES) regions (23.7% vs. 21.5%; p = 0.005) and more likely to receive tyrosine kinase inhibitors (TKIs) (37.6% vs. 23.6%; p &lt; 0.001). Adherence was high overall with 74.6% of members achieving a PDC ≥ 0.85; however, members with dose modifications were less likely to be adherent (69.7% vs. 80.0%; p &lt; 0.001). Holding other confounders constant, having a dose modification was associated with a decreased likelihood of adherence (Odds Ratio [95% Confidence Interval]: 0.6 [0.55-0.65]; p &lt; 0.001). Conclusions: Dose modification was associated with significant decreases in adherence to oral oncolytic medications. Interventions designed to minimize dose modifications or to provide additional member support during a dose modification may optimize oral oncolytic adherence.

Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer.

4503 Background: Enfortumab vedotin (EV) is approved in combination with pembrolizumab and as a monotherapy for locally advanced or metastatic urothelial cancer (la/mUC). EV, alone and in combination with pembrolizumab, has demonstrated an OS benefit and a generally manageable safety profile in patients (pts) with previously treated or untreated la/mUC. Dose modifications, including reductions and interruptions, are recommended to manage EV-related AEs. This analysis evaluates the association between EV plasma exposure, which is impacted by dose modifications, and safety and efficacy outcomes. Methods: Characterization of dose- and exposure-response for efficacy and exposure-response for safety outcomes included pts in EV-101 (EV monotherapy 0.75, 1.0, and 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle [3Q4W]), EV-201, and EV-301 (EV monotherapy 1.25 mg/kg 3Q4W). Time-averaged exposure up to an event of interest, Cavg, was computed using a population PK model. PK assessment included multiple samples in first 2 cycles, and pre-dose samples in subsequent cycles. Results: Dose modifications were common, including dose reductions to 1.0 mg/kg (EV-201 42.1%; EV-301 35.1%) and 0.75 mg/kg (EV-201 13.6%; EV-301 11.1%). EV showed consistent improvement in median PFS and OS vs chemotherapy across all exposure quartiles in EV-301 inclusive of dose modifications (Table). Greater initial EV exposure in the first 2 cycles was associated with a higher ORR and was consistent with dose-response (0.75 mg/kg 21.4% [sample size {n} = 14]; 1.0 mg/kg 18.5% [n = 27]; 1.25 mg/kg 40-51.1% across studies [n = 613]). Lower EV exposure was associated with lower risk of EV-related Grade ≥3 rash or skin reactions, Grade ≥2 peripheral neuropathy, and Grade ≥3 hyperglycemia (P&lt;0.0001 for all). Conclusions: EV improved PFS and OS outcomes vs chemotherapy in pts with la/mUC across all exposure quartiles. The starting dose of 1.25 mg/kg 3Q4W resulted in EV exposure that maximized likelihood of response. Recommended dose modifications are effective for managing EV-related AEs and should be used as clinically indicated. Clinical trial information: NCT02091999 , NCT03219333 , and NCT03474107 . [Table: see text]

Prognostic analysis and outcomes of metastatic pancreatic cancer patients receiving nab-paclitaxel plus gemcitabine as second or later-line treatment.

Pancreatic cancer (PC) first-line therapy often consists of polychemotherapy regimens, but choosing a second-line therapy after disease progression, especially following first-line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab-paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. AG was well-tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second-line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first-line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first-line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second-line OS and PFS. This study represents the largest real-world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first-line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first-line therapy.

Phase IB study of tovorafenib for children with relapsed/recurrent low-grade gliomas and other MAPK pathway activated tumors.

10001 Background: LGGs present a therapeutic challenge often occurring in areas of brain and spine not amenable to resection and carrying high morbidity with currently available therapies. The majority harbor alterations in the MAPK pathway. Our study (NCT03429803) aimed to establish the recommended phase 2 dose (RP2D) and assess the safety, tolerability and preliminary efficacy of type II RAF-inhibitor tovorafenib in such tumors. Methods: Eligible patients were &gt; 1 year and &lt; 25 years old with radiographically recurrent/progressive MAPK pathway-altered tumors. We applied a novel 2S-Sub-TITE design to determine a RP2D with posterior probability of toxicity closest to the 20% target for patients with BSA ≤1.5 and &gt; 1.5 m2 based on preliminary exposure-efficacy data. Toxicities were graded according to CTCAE version 5. Patients with complete response (CR), partial response (PR) or stable disease (SD) were designated responders. Results: We treated 35 eligible patients, including 20 KIAA1549:BRAF-, 9 BRAF V600E- and 1 FGFR1-altered tumors; 5 possessed novel RAF fusions. Histologically, there were 27 grade 1 gliomas, 3 anaplastic pleomorphic xanthoastrocytomas, 3 pilomyxoid astrocytomas, 1 high-grade glioma and 1 soft tissue sarcoma. There were 6 grade 3 DLTs (2 fatigue, 3 rash, 1 menorrhagia) in 30 evaluable patients: 3 in each BSA subgroup, all at 530 mg/m2/dose. Using AAP guidelines for minimum pubertal peak growth velocities (GV) in males (7 cm/year) and females (6 cm/year), decreased GV (median 0.09 cm/year; range 0.02-0.3) was an unexpected, related AE observed in all 13 of 13 pre-pubertal females &lt; 14 or males &lt; 16 years of age receiving &gt;6 months of protocol 1B therapy. Three of 13 patients with decreased GV were treated at 420 mg/m2. Three of the remaining 10 patients with decreased GV originally treated at 530 mg/m2 were dose reduced for other toxicities and hence, 6 of 13 patients with decreased GV were treated at the RP2D. For patients with follow-up data available, GV appears to show recovery off drug. The 2S-Sub-TITE model recommended 530 mg/m2 for BSA ≤1.5m2 and 420 mg/m2 for BSA &gt; 1.5m2. Dose modifications were required in 8/22 versus 1/13 patients treated at 530 and 420 mg/m2, respectively. Twenty-seven of 35 patients were evaluable for objective response performed by an independent single reader. Overall, 25 patients had SD, PR or CR with median duration of response of 11.3 months (range 0.03-35.4) at data cutoff. Conclusions: Oral weekly tovorafenib is well tolerated and shows preliminary efficacy. Decreased GV was observed in pre-pubertal patients on drug and warrants further investigation to understand the mechanism of action. Based on the number of dose modifications required for toxicity, the chosen RP2D for weekly oral dosing of tovorafenib was 420 mg/m2. Clinical trial information: NCT03429803 .

Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma

BackgroundBelantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies.MethodsIn this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)–negative status.ResultsIn total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved.ConclusionsAs compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.)

Preventing chemotherapy-induced peripheral neuropathy with acupuncture, a multinational parallel randomized controlled trials project (PACT).

TPS12156 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant challenge for patients (pts) with breast cancer treated with taxanes and platinum compounds. CIPN severely affects quality of life, leading to paresthesia and pain, and often results in dose modifications and discontinuation of treatment. Although preliminary trials suggest the effectiveness of acupuncture in managing existing symptoms of CIPN, the use of acupuncture to prevent CIPN is not well studied. Prior studies provide inconclusive results, underscoring the need for more rigorous investigation. We designed an international study, PACT, to evaluate the impact of acupuncture on the prevention of CIPN in breast cancer pts who undergo adjuvant or neoadjuvant taxane-based chemotherapy. Methods: PACT is a coordinated multi-national study consisting of three parallel randomized trials in USA, China, and South Korea, using the same inclusion/exclusion criteria, randomization, interventions, and validated measures. PACT is designed to evaluate the effectiveness of acupuncture in preventing CIPN in pts undergoing taxane-based chemotherapy for early-stage breast cancer. Participants include pts with newly diagnosed stage I-III breast cancer without preexisting neuropathy, scheduled for adjuvant or neoadjuvant taxane-based chemotherapy. Target enrollment is 140 pts from three sites: Dana-Farber Cancer Institute (USA) (n=100), Jiangsu Province Hospital of Chinese Medicine (China) (n = 20) and the Daegu Catholic University Medical Center (South Korea) (n=20), randomized (1:1) to the acupuncture arm or a control. The acupuncture arm receives a standardized protocol of 1-2 sessions per week for 12 weeks (total of 14 sessions). The control arm receives relaxation exercises with nature scenery videos for 14 sessions. The follow-up period for both arms is 12 weeks. Main measures include The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20, QLQ-30 and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) CIPN items. The primary outcome measure is the change in CIPN severity, assessed using the EORTC QLQ-CIPN20 sensory subscale, between baseline and week 12, with secondary outcomes including occurrence of CIPN and maximum CIPN scores, pain, sleep quality, and overall quality of life. A planned pooled analysis of individual patient data will be performed. The ethics review committee of each site has approved the study. Today, 89 (64%) of the planned 140 participants have been enrolled. Clinical trial information: NCT05528263 , ChiCTR2200066714, KCT0008470.

Real-world analysis of belantamab mafodotin (belamaf): Care patterns in relapsed/refractory multiple myeloma.

e19507 Background: Belamaf is an anti-B cell maturation antigen immunoconjugate for relapsed/refractory multiple myeloma that has shown efficacy and safety in the DREAMM clinical trials. Additional long-term real-world data on its use patterns, efficacy, and tolerability are needed. Methods: This retrospective review (NCT05986682) analyzed adults with multiple myeloma receiving ongoing care at Duke Cancer Institute who began belamaf monotherapy (not in a clinical trial) between 8/5/2020 and 11/22/2022. We abstracted data for 30 patients through 9/18/2023. We described baseline clinical characteristics, disease response (per International Myeloma Working Group [IMWG] criteria, as possible given available marrow biopsy data), belamaf use patterns, and ocular adverse events (AEs) (per the Keratopathy Visual Acuity [KVA] scale). Results: Our sample was 53% (n=16) female, 47% (14) White, and 47% (14) Black; median age was 68 years at the beginning of belamaf therapy. 67% (20) had ≥4 prior lines of therapy (median: 4, min-max: 2-19), 87% (26) were triple-/quad-/penta-refractory, and 23% (7) had high-risk cytogenetics (per IMWG). Overall response rate (ORR) was 67% (11 very good partial response, 9 partial response). Median (min-max) time to best response was 1.5 (0.7-9.9) months. Median (min-max) response duration was 9.8 (1.1-20.2) months. Progression occurred in 73% (22) of patients; median progression-free survival (PFS) was 8.4 months (95% CI 6.6-12.7). Median overall survival was not reached. Median (min-max) number of cycles was 6.5 (2-13). 63% of patients (19) had a dose reduction from 2.5 to 1.9 mg/kg; 65% (13) were due to corneal AEs and 30% (6) due to hematologic AEs. 93% (28) had ≥1 cycle delay, and the median (min-max) number of delays was 5 (1-14); 85% of delays (n=153) were due to corneal AEs. Cycle length changed for 33% (10) from every 3 weeks to every 4 (1) or 6 (9) weeks; 91% (n=10) of cases were due to corneal AEs. 93% (28) had keratopathy (any grade); among all events (n=323), 2% were grade ≥3. Median (min-max) time to resolution of grade ≥2 keratopathies was 6 (2-22) weeks. 90% (27) experienced a visual acuity change; among all events (n=244), 3.3% were grade ≥3. Median (min-max) time to resolution of grade ≥2 visual acuity events was 6 (2.9-53) weeks. The most common ocular symptoms were blurry vision (53% of symptoms), dry eyes (17%), and photophobia (14%). Belamaf was discontinued in 13% (4) due to ocular AEs and 20% (6) to patient/physician choice or other reason. Median (min-max) time to last dose/discontinuation was 9.3 (0.7-21.6) months. Conclusions: In our study, ORR and median PFS were greater than other real-world studies. Corneal AEs were also more common, but severity was consistent with these and DREAMM-3 findings. Despite a higher rate of dose reductions and delays than other real-world studies, our study adds promise to the benefit of belamaf over an extended time with dose modifications.