Fluconazole in Hypercalciuric Patients with Increased 1,25(OH)2D Levels: The Prospective, Randomized, Placebo-Controlled, Double Blind FLUCOLITH Trial.

BackgroundHypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels.MethodsThe FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double blind trial. A total of 60 patients (10-60years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/d), increased 1,25(OH)2D levels (> 150 pmol/L) and 25-OH-D levels >20 nmol/L, will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-hour calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-hour calciuria in patients who still display at W16 a 24-hour hypercalciuria. DiscussionThe current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the “off-label” use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients. Trial RegistrationClinicalTrial.gov, ID: identifier: NCT04495608. Registered on July 23rd, 2020

345 Phase I/II trial of cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies (CAMILLA): phase Ib safety and efficacy results

BackgroundCabozantinib is a multi-tyrosine kinase inhibitor primarily targeting VEGFR, MET, and AXL. These targets promote a tumor immune permissive microenvironment. Cabozantinib has demonstrated immunomodulatory properties & clinical synergy when paired with PD-L1 inhibitors such as durvalumab. Here, we present final results of phase Ib of the Camilla trial assessing cabozantinib plus durvalumab in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), and hepatocellular carcinoma (HCC). This is an investigator-initiated trial funded by Exelixis & Astrazeneca.MethodsPatients were administered cabozantinib + durvalumab in a dose escalation (3+3) then expansion to find the Dose Limiting Toxicities (DLTs), Recommended Phase 2 Dose (RP2D), ORR, PFS, and OS. Subgroup analysis was conducted to assess efficacy in patients with PD-L1 Combined Positive Score (CPS) ≥ 5. Dosing of cabozantinib was 20mg QD, 40mg QD, and 60mg QD PO in the 1st, 2nd, and 3rd cohorts. Dosing of durvalumab was 1500mg IV Q4W in all cohorts. DLT window was 28 days. Treatment beyond progression was allowed following modified RECIST v1.1 criteria.Results35 patients (14F, 21M), median age 53 years (range 27–79) were enrolled. 10 patients had GEA, 20 had CRC, and 5 had HCC; none had MMR deficiency. Median number of prior systemic therapies was 3 (range 0–3). No DLTs were observed during dose escalation. Per mature tolerability data, 11/14 patients receiving cabozantinib 60mg required dose-reduction post cycle 2 to 40mg. RP2D was determined to be cabozantinib 40mg QD plus durvalumab 1500mg Q4W. Of the 247 observed Treatment-Related Adverse Events (TRAEs), 10% (24) were grade≥3. Most common TRAEs were grade 1–2 fatigue (57%), nausea (43%), anorexia (40%), diarrhea (37%), transaminitis (34%), hand-foot syndrome (23%), & weight loss (23%). 2 patients each developed grade≥3 fatigue, weight loss, & abdominal pain. Overall, 30 pts were evaluable for efficacy. ORR 26.7%; DCR 83.3%; median PFS 4.5 months; 6-month PFS 36.7%; and median OS 9.1 months. 12 patients had PD-L1 CPS ≥5. In this subgroup, ORR 33.33%; DCR 91.67%; median PFS 6.13 months; 6-month PFS 50%; and median OS was not reached.ConclusionsCabozantinib plus durvalumab demonstrated promising efficacy and was fairly tolerated without new safety signals. High PD-L1 expression defined as CPS ≥ 5 was associated with improved efficacy & survival. The phase II multi-cohort part of the trial is currently ongoing.Trial RegistrationNCT03539822Ethics ApprovalThe study was approved by the participating site’s local IRB.ConsentAll study participants granted a written informed consent prior to treatment initiation.

Alloreactive Immune Response Associated to Human Mesenchymal Stromal Cells Treatment: A Systematic Review

The well-known immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) are the reason why they are being used for the treatment of many diseases. Because they are considered hypoimmunogenic, MSCs treatments are performed without considering histocompatibility barriers and without anticipating possible immune rejections. However, recent preclinical studies describe the generation of alloantibodies and the immune rejection of MSCs. This has led to an increasing number of clinical trials evaluating the immunological profile of patients after treatment with MSCs. The objective of this systematic review was to evaluate the generation of donor specific antibodies (DSA) after allogeneic MSC (allo-MSC) therapy and the impact on safety or tolerability. Data from 555 patients were included in the systematic review, 356 were treated with allo-MSC and the rest were treated with placebo or control drugs. A mean of 11.51% of allo-MSC-treated patients developed DSA. Specifically, 14.95% of these patients developed DSA and 6.33% of them developed cPRA. Neither the production of DSA after treatment nor the presence of DSA at baseline (presensitization) were correlated with safety and/or tolerability of the treatment. The number of doses administrated and human leucocyte antigen (HLA) mismatches between donor and recipient did not affect the production of DSA. The safety of allo-MSC therapy has been proved in all the studies and the generation of alloantibodies might not have clinical relevance. However, there are very few studies in the area. More studies with adequate designs are needed to confirm these results.

Graphical representations of patient tolerability data: Recommendations from the National Cancer Institute (NCI) Cancer Moonshot Standardization Working Group.

e18612 Background: Effective communication of treatment tolerability data is essential for clinical decision making and improved patient outcomes, yet standardized approaches to the analysis and visualization of tolerability data in cancer clinical trials are currently limited. To address this need, the Standardization Working Group (SWG) was established within the NCI Cancer Moonshot Tolerability Consortium. This abstract describes the SWG’s initiative to develop a publicly accessible online toolkit with a comprehensive set of guidelines, references, and resources for graphical displays of tolerability data. Methods: A multidisciplinary group of PRO researchers including biostatisticians, clinicians, epidemiologists, and representatives from the NCI and FDA convened monthly to discuss toolkit development and content. Considerations for standardization of graphical displays of tolerability data included (1) types of graphical displays, (2) incorporation of missing data, (3) labeling and color schemes, and (4) software to produce graphical displays. For consistency, considerations of tolerability relied on the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE), which includes 124 items assessing the frequency, severity, interference, and/or presence of 78 symptomatic adverse events. Graphical displays were generated using simulated PRO-CTCAE data and summarized by composite score (range 0-3).Color schemes that were Section 508 compliant and color blindness accessible were created. Surveys were distributed to 68 consortium members to assess preferences and interpretability of the graphical displays. Results: The SWG created graphical displays for PRO-CTCAE data, including bar charts, butterfly plots, and Sankey diagrams and compiled SAS macros and R functions to do so. Graphical displays made available in the toolkit maximize the use of PRO-CTCAE data, incorporate missingness, support between-arm comparisons, and present data longitudinally over treatment cycles or study timepoints. Survey results for labeling and color schemes were summarized and informed a list of short labels for PRO-CTCAE items (e.g., “radiation burns” for “skin burns from radiation”) and standardized color schemes for use in graphical displays. Survey results were also summarized to provide insight into PRO researchers’ ability to accurately interpret the graphical displays. Conclusions: Standardizinggraphical displays is important for improving the communication and interpretation of tolerability data. The type of graphical display used depends on the purpose of the analysis and should be tailored to the intended audience, including patients. This toolkit will provide a comprehensive resource with best practice recommendations.

Use of Intramuscular Chlorpromazine Versus Intramuscular Olanzapine for the Management of Acute Agitation and Aggression in Youth

OBJECTIVES In the inpatient psychiatric setting, one treatment strategy used to manage acute agitation in youth includes administration of IM antipsychotics. The aim of this study was to compare the effectiveness and safety of IM chlorpromazine versus IM olanzapine in treating aggression in youth. METHODS We conducted a retrospective chart review of patients younger than 18 years hospitalized in the inpatient psychiatric unit who received either IM chlorpromazine or IM olanzapine for acute agitation. Demographic, efficacy, and tolerability data were collected using the electronic health record EPIC. The primary outcome was change from baseline to end point in the Behavioral Activity Rating Scale (BARS) score. BARS was applied retrospectively using nursing and physician documentation to evaluate for clinical response. RESULTS Among 145 patients who met the inclusion criteria, 72 received IM chlorpromazine, compared with 73 who received IM olanzapine. The mean change in BARS score (before and after IM antipsychotic) was greater with olanzapine (3.58 ± 0.99) than with chlorpromazine (3.07 ± 1.18, p = 0.006). The target BARS score of 4 was achieved more frequently with chlorpromazine (45.8%) than with olanzapine (24.7%, p < 0.008). Coadministration of IM diphenhydramine occurred significantly more often in the olanzapine group than in the chlorpromazine group (71.2% vs 36.1%, p < 0.001). CONCLUSIONS Management of acute agitation with IM olanzapine resulted in a greater change in BARS score, despite more youth requiring coadministration with diphenhydramine. In comparison, IM chlorpromazine demonstrated a higher likelihood of returning patients to baseline. Study results suggest tolerability of IM chlorpromazine and olanzapine.

Tolerability Assessment of Formulation pH in New Zealand White Rabbits Following Intravitreal Administration

Development of intravitreal drugs presents several challenges due to the delicate ocular environment and volume constraints of what can be safely administered in the eye. Formulation development of intravitreally administered drugs may necessitate the use of nonphysiological pH in order to accommodate manufacturing processes or achieve favorable drug properties. Clinical and nonclinical data show that intravitreal drugs formulated in the pH 5.5 to 7.4 range are well tolerated. The aim of this study was to provide ocular toxicity data for formulations in the pH 4.0 to 5.5 range following intravitreal administration in New Zealand White rabbits. This range was evaluated as part of formulation development for an intravitreal drug that necessitated the use of pH outside the available tolerability data for formulations. Toxicity was assessed by ophthalmic examinations, intraocular pressure (IOP) measurement, clinical observations, body weights, and microscopic analysis of ocular tissue. Histidine chloride pH 5.0 to 5.5 and acetate chloride pH 4.0 to 5.0 solutions were well tolerated, and no test article-related ocular inflammation, IOP changes, or gross or microscopic findings were observed in any eye. The data presented here add to the knowledge of pH ranges that can be explored for intravitreal drug formulation development.

The adjuvant use of capecitabine for residual disease following pre-operative chemotherapy for breast cancer: Challenges applying CREATE-X to a US population

Introduction The CREATE-X study, conducted in Japan and South Korea, established capecitabine as an adjuvant treatment option for patients with triple negative breast cancer (TNBC) who have residual disease (RD) following neoadjuvant anthracycline or taxane-based chemotherapy. However, there are no reports on the tolerability and outcomes of adjuvant capecitabine in the US setting following publication of the CREATE-X data. Methods We retrospectively collected treatment and tolerability data from the medical records of the first 23 TNBC patients who received adjuvant capecitabine for RD post neoadjuvant chemotherapy at our institution. Disease-free survival was assessed using the Kaplan-Meier method. Results The median starting dosage of capecitabine was 1871 mg/m2/day, most commonly divided into two daily doses on days 1-14 of each 21 day cycle. 34.8% of patients completed the treatment as prescribed. Side effects associated with treatment were common with 69.6% of patients experiencing hand-foot syndrome, 39.1% of patients experiencing diarrhea, and 13.0% of patients requiring hospitalization for side effects. Of 23 patients treated with adjuvant capecitabine, 34.8% completed the planned dose, 30.4% completed with dose reduction, and 34.8% discontinued early. At a median follow-up time of 14 months, the median disease-free survival was 22 months, with 30.4% of patients experiencing recurrence. Conclusion Tolerability was poor overall compared to the CREATE-X cohort. Administering adjuvant capecitabine for TNBC patients with residual disease in the United States is challenging given differences in tolerability. More research is needed to understand how poor tolerability will affect the efficacy of this approach in the US population.

144. MSG-15: Pharmacokinetic (PK), Adverse Events (AEs), and Tolerability Data from an Open Label Randomized Clinical Trial (RCT) Comparing Oral Suba-itraconazole (SUBA-ITC) to Conventional Itraconazole (C-ITC) for Treatment of Endemic Mycosis (EM)

Background C-ITC is a drug of choice for non-life-threatening, non-CNS histoplasmosis, blastomycosis, sporotrichosis, coccidioidomycosis and other EM. Oral C-ITC is problematic due to inconsistent absorption often leading to sub-therapeutic serum levels. SUBA-ITC is an FDA approved formulation which utilizes nanotechnology to provide more consistent absorption when compared to C-ITC. We performed an open-label RCT comparing SUBA-ITC to C-ITC for non-life-threatening non-CNS EM, and is the first US based RCT examining SUBA-ITC. Herein we report the PK during the first 6 wks of study therapy (rx) and drug-related AEs and tolerability throughout the course of rx. Methods Subjects with a proven or probable EM, who had received <14 days prior antifungal tx, and were able to take po meds were eligible. Those with life-threatening and CNS disease or prohibited meds were excluded. Subjects were randomized to SUBA-ITC 130 mg or C-ITC 200mg, both PO BID, for up to 6 mo. All subjects received loading doses x 3d. Clinical assessment was performed on d 7, 14, 28, 42, 84, and 180. PK and safety evaluations were performed on d 7, 14 and 42. Serum levels and AUC were calculated and demonstrated using combined ITC and hydroxy-ITC measurements. Tolerability was based on subject ability to remain on rx. Results 62 subjects are included in this analysis (31 each in SUBA-ITC and C-ITC, respectively). Median serum levels of ITC + hydroxy-ITC at d 7, 14 and 42 were consistently higher in the SUBA-ITC arm (Fig 1, p=0.8, NS). Combined AUC (ITC+hydroxy-ITC) were 2951 and 2845 for SUBA-ITC and C-ITC, respectively (NS). 4 subjects in each arm had sub-therapeutic d 7 levels (< 1000ng/ml). Drug-related AEs and tolerability were similar in both arms (Table 1). Lower extremity edema, hypertension, nausea, and anorexia were the most common AEs. Premature study withdrawal was seen in 12 (19%) subjects overall (5 and 7 subjects, respectively on SUBA-ITC and C-ITC). Figure 1 Conclusion SUBA-ITC dosed at 130 mg BID PO is safe, well-tolerated, and consistently leads to combined serum ITC/hydroxy-ITC levels and AUC that are higher (NS) when compared to C-ITC 200 mg BID. Moreover, compared to C-ITC, SUBA-ITC achieves these serum levels when administered at substantially lower daily doses (130mg BID vs 200 mg BID). Disclosures Peter G. Pappas, MD, Mayne Pharma (Scientific Research Study Investigator) Andrej Spec, MD, MSCI, Mayne (Consultant, Grant/Research Support) Marisa H. Miceli, MD, FIDSA, SCYNEXIS, Inc. (Advisor or Review Panel member) Laurie Proia, MD, Mayne Pharma (Scientific Research Study Investigator) Ana Belen Arauz, MD, Mayne Pharma (Scientific Research Study Investigator) Justin Hayes, MD, Mayne Pharma (Grant/Research Support) Alisa Peinhardt, MAIS, BSN, Mycoses Study Group Education and Research Consortium (Consultant)

Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.

478 Background: The programmed death-1 inhibitor NIVO had durable responses and a manageable safety profile in pts with aHCC in CheckMate 040 (NCT01658878; El-Khoueiry et al. Lancet 2017) and is approved in the United States, Canada, Australia, and elsewhere for sorafenib (SOR)-treated pts with aHCC. In another CheckMate 040 cohort, NIVO + IPI combination therapy had durable responses in SOR-treated pts with aHCC, with objective response rates (ORRs) > 30% in each dosing arm (Yau et al. J Clin Oncol 2019). CABO is also approved for SOR-treated pts with aHCC; a pivotal phase 3 trial reported median overall survival (OS) of 10.2 mo (Abou-Alfa et al. N Engl J Med 2018). This is the first report of efficacy and safety of NIVO + CABO +/- IPI (doublet and triplet) combinations in pts with aHCC. Methods: SOR-naive or -experienced pts with aHCC were randomized to 2 arms: [1] NIVO 240 mg Q2W + CABO 40 mg daily or [2] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W + CABO 40 mg daily. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included ORR (investigator assessed using RECIST v1.1) and safety/tolerability. Data cutoff was January 2019. Results: 71 pts were randomized to NIVO + CABO (n = 36) or NIVO + IPI + CABO (n = 35). Investigator-assessed ORR was 17% (6 pts with partial response [PR]) in the NIVO + CABO arm and 26% (9 pts with PR) in the NIVO + IPI + CABO arm. Disease control rate was 81% for the NIVO + CABO arm and 83% for the NIVO + IPI + CABO arm; median progression-free survival was 5.5 mo for the NIVO + CABO arm and 6.8 mo for the NIVO + IPI + CABO arm. Median OS was not reached in either arm. Grade 3-4 treatment-related adverse events (TRAEs) were reported in 15 pts (42%) in the NIVO + CABO arm and 25 pts (71%) in the NIVO + IPI + CABO arm and led to discontinuation in 1 (3%) and 7 (20%) pts, respectively. No new safety signals were observed in either arm. Updated data describing the efficacy and safety of the combinations will be shown. Conclusions: In pts with aHCC, NIVO + CABO +/- IPI combination therapy led to clinically meaningful responses. Although the triplet had a higher rate of TRAEs observed than the doublet regimen, the majority of AEs were manageable and reversible. Clinical trial information: NCT01658878.