Dexamethasone Mouthwash Research Articles

Abstract C020: First-in-human phase 1/1b trial of the first-in-class bi-steric mTORC1-selective inhibitor RMC-5552 in patients with advanced solid tumors

Abstract Activation of the mTOR pathway plays a role in the oncogenesis and progression of many cancer types, and is frequently co-altered in RAS-driven tumors. First-generation mTORC1-selective inhibitors were limited by incomplete inhibition of 4EBP1 phosphorylation, while second-generation pan-mTOR inhibitors had a low therapeutic index due to mTORC2-mediated toxicity such as hyperglycemia. RMC-5552 is a first-in-class third-generation bi-steric mTOR inhibitor that is mTORC1-selective via its FKBP12-binding moiety and potently inhibits phosphorylation of the 4EBP1 tumor suppressor via a linked ATP-competitive moiety, addressing these key limitations of prior mTOR inhibitors in preclinical models. RMC-5552 is being investigated in a Phase I/Ib study (NCT04774952). Eligible patients (pts) were ≥18 yrs old with ECOG 0-1 and had advanced solid tumors that had failed or were ineligible for standard-of-care treatments. Pts received RMC-5552 as a weekly infusion. To address mucositis, a common toxicity in pts treated with mTOR inhibitors, pts prophylactically used dexamethasone mouthwash either alone or with tacrolimus mouthwash (TM), which binds to the RMC-5552 presenter protein FKBP12. Objectives included assessment of safety/tolerability (CTCAEv5), defining the maximum tolerated and recommended Phase 2 doses, pharmacokinetics, and preliminary efficacy (RECIST v1.1). As of June 12, 2023, 47 pts have been evaluated at 6 dose levels from 1.6 mg to 12 mg. The most common (> 20%) treatment-related adverse events (TRAE, any grade) were stomatitis/mucositis (45%), fatigue (40%), nausea (38%), decreased appetite (32%), and vomiting (23%). Treatment-related events of hyperglycemia occurred in 4% of pts (both grade 2) and were not dose limiting. The most common grade 3 TRAE at dose levels ≥6 mg was mucositis/stomatitis, which was dose-dependent and limited tolerability in the absence of TM. Between 8 and 12 mg, the rate of treatment related stomatitis/mucositis was 65% (15% grade 3) in pts treated without TM (N = 20) versus 30% (no grade 3) in pts treated with TM (N = 10). TM prophylaxis enabled dose escalation beyond dose levels previously considered intolerable due to mucositis (10-12 mg; escalation ongoing), and unbound plasma exposures at 8-12 mg were within the range that induced significant anti-tumor activity in preclinical models. The disease control rate was 67% among efficacy evaluable pts (N = 39). One pt with a salivary gland tumor harboring a PTEN mutation had a confirmed partial response (PR) with 78% reduction and 16 months duration of response. In addition, molecular responses of circulating tumor DNA were observed in pts with mTOR pathway variants. Updated efficacy results will be presented. These early data indicate that RMC-5552 monotherapy is tolerated at doses predicted to be efficacious, and that selective inhibition of mTORC1 alleviates mTORC2-mediated toxicity. Dose escalation is ongoing, and mucositis prophylaxis has enabled further dose intensification for future combination studies with RAS(ON) inhibitors. Citation Format: Alison M Schram, Abdul Rafeh Naqash, Eric B Haura, Jonathan W Riess, Susanna V Ulahannan, Sai-Hong I Ou, Anna Capasso, Pamela N Munster, Michael L Cheng, W Clay Gustafson, Bojena Bitman, Sumit Kar, Zhican Wang, Lin Tao, Justin G Meyerowitz, Howard A Burris. First-in-human phase 1/1b trial of the first-in-class bi-steric mTORC1-selective inhibitor RMC-5552 in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C020.

Effectiveness and safety of a novel dexamethasone mouthwash formulation in managing stomatitis in cancer patients

ObjectiveTo present a new dexamethasone mouthwash formulation and analyze its effectiveness and safety among patients receiving stomatitis-producing antineoplastic agents. MethodProspective observational study conducted in a university hospital between March 2017 and November 2019. Consecutive patients starting everolimus were enrolled. Patients were instructed to rinse dexamethasone mouthwash formulation twice daily until discontinuation of everolimus. A second cohort of patients with existing stomatitis induced by high probability of producing stomatitis chemotherapy therapies was also recruited to assess treatment effectiveness. Effectiveness and safety of dexamethasone mouthwash formulation was assessed. ResultsDexamethasone mouthwash formulation was prescribed in nine patients as prophylaxis. Six patients were diagnosed with breast cancer, two with neuroendocrine tumor and one with renal cell carcinoma. Four patients developed mild stomatitis (grade 1-2) and three patients discontinued everolimus due to other treatment-related adverse events. In addition, dexamethasone mouthwash formulation was prescribed as treatment in five patients with existing stomatitis. All patients achieved a significant reduction in the severity of stomatitis after starting the dexamethasone mouthwash formulation. In both cohorts, dexamethasone mouthwash formulation was well tolerated and neither dose reduction nor discontinuation related to stomatitis was required. ConclusionsDexamethasone mouthwash formulation could be considered as a suitable alternative for stomatitis management.

Significant efficacy of short-course, low-concentration betamethasone mouthwash therapy for severe erosive oral lichen planus: a randomized controlled trial.

To evaluate the short-term efficacy of low-concentration betamethasone mouthwash for severe erosive oral lichen planus (EOLP). In this randomized, investigator-blind, positive-controlled trial, OLP patients with erosive lesions received betamethasone mouthwash (0.137 mg/mL) or dexamethasone mouthwash (0.181 mg/mL) three times daily for 2 or 4 weeks and were followed up for 3 months to observe recurrence. The primary outcome was the week-2 reduction in erosive area. Fifty-seven participants were randomized to betamethasone (n = 29) and dexamethasone (n = 28). At week 2, participants using betamethasone (n = 28) experienced a greater reduction in erosive area than gargling with dexamethasone (n = 26). Similarly, secondary outcomes, including the healing proportion of erosions, reduced pain level, reduction in atrophic area, Thongprasom score, and recurrence interval, showed the superiority of betamethasone. At week 4, betamethasone (n = 7) was not superior to dexamethasone (n = 15) in further reducing lesional area and pain level. No serious adverse events were documented. The 0.137 mg/mL compound betamethasone mouthwash exhibited significant efficacy in rapidly enhancing erosion healing within 2 weeks and extending the recurrence interval with a good safety profile. This study proved the significant efficacy of short-course 0.137 mg/mL betamethasone mouthwash therapy for treating erosion and pain, providing a novel topical agent for patients with severe EOLP. This study was prospectively registered at the International Clinical Trials Registry Platform ( ChiCTR1800016507 ) on 5 June 2018.

Abstract P3-01-04: A real-world evidence study of everolimus plus endocrine therapy beyond CDK4/6 inhibitors for HR+/HER2- advanced breast cancer

Abstract Introduction Since the approval a decade ago of everolimus in combination with endocrine therapy (ET), the treatment landscape of metastatic breast cancer (mBC) has changed dramatically. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS) below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. Methods We performed a retrospective observational study of patients with mBC treated with everolimus between September 2011 and April 2022 in 4 Spanish hospitals. Clinical and demographic data were collected from medical records. Our main objective was to estimate the median progression-free survival (mPFS) for everolimus + ET in patients previously treated with a CDK4/6 inhibitor. We also collected the adverse events (AE) related to everolimus. Quantitative variables were summarized with medians (range), and qualitative variables with proportions. We used the Kaplan-Meier method for survival estimates. Results We identified a total of 297 mBC patients treated with everolimus plus ET. The median follow-up time was 20 months (interquartile range: 1 – 97 months). In this cohort, the median age at diagnosis was 49 years (26 – 84 years). At the moment of starting everolimus, the median number of previous lines of treatment was 2 (0 – 12), 22% of patients were ‘de novo’ metastatic, 67% presented visceral involvement, 40% had received previous chemotherapy for advanced disease, and 51% (n=152) had received a previous CDK4/6 inhibitor. The ET combined with everolimus was exemestane (77%), fulvestrant (18%), and tamoxifen (5%). 45% of patients were alive at data cut-off. In patients previously treated with a CDK4/6 inhibitor, the estimated median PFS (mPFS) was 5.9 months (95%CI: 5.0 – 7.8 months). In patients without visceral involvement (n=52), mPFS was 7.2 months (95%CI: 5.5 – 11.0 months), and 5.6 months (95%CI: 3.9 – 7.8 months) in the presence of visceral metastasis (n=100). In patients without previous chemotherapy in the metastatic setting (n=109), mPFS was 7.2 months (95%CI: 5.9 – 8.4 months), and 4.6 months (95%CI: 3.1 – 5.7 months) for patients who had received previous chemotherapy (n=43). For patients without a previous CDK4/6 inhibitor (n=145), the median PFS was 8.3 months (95%CI: 6.4 – 10.3 months). Everolimus starting doses were 10 mg (83%), 5 mg (15%), and 7.5 mg (2%). Dexamethasone mouthwash was used by 44% of patients. The most frequent AE were mucositis (51%; 3% grade 3), anemia (41%; 3% grade 3), hyperglycemia (34%; 2% grade 3), rash (28%; 2% grade 3), neumonitis (21%; 2% grade 3), and diarrhea (17%; 1% grade 3). There were no grade 4-5 adverse events. Dose reduction was made in 35% of patients, and in 16% of patients the treatment was discontinued due to toxicity. Conclusions In our cohort, the use of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor showed a clinically significant benefit in terms of PFS, especially in patients without visceral metastasis, and no previous chemotherapy for advanced disease. In this real-world study, the toxicity profile of everolimus was manageable. Citation Format: Rodrigo Sánchez-Bayona, Manuel Alva, Alfonso López de sa, Yolanda Jerez Gilarranz, Ana Sánchez de torre, Pablo Tolosa, Alicia de luna, Sara López-Tarruella, Laura Lema, Fernando Moreno, Isabel Echavarria, Ainhoa Madariaga, Javier Benítez, Blanca Herrero, Macarena Rey, Justo Ortega, Salvador Gámez, Andrea Modrego, Rocío Martín Lozano, Luis Figuero-Pérez, Roberto Jiménez, Marta González Sevilla, Irene González, Marianela Bringas Beranek, María de toro, Tatiana Massarrah, María del Monte-Millán, Marina Pinardo, Luis Manso, Coralia Bueno-Muiño, José Ángel García-Sáenz, Miguel Martín, Eva Ciruelos. A real-world evidence study of everolimus plus endocrine therapy beyond CDK4/6 inhibitors for HR+/HER2- advanced 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 P3-01-04.

Dexamethasone to prevent everolimus-induced stomatitis (Alliance MIST Trial: A221701)

mTOR inhibitors such as everolimus may cause oral stomatitis, often a dose-limiting toxicity. Prior clinical research has suggested that a dexamethasone mouth rinse might help prevent and/or treat this. Alliance A221701 was a randomized phase III trial of patients initiating 10 mg daily oral everolimus that compared dexamethasone mouthwash taken preventively (initial dexamethasone group) versus therapeutically (initial placebo group) to assess two coprimary endpoints: the incidence of mTOR inhibitor-associated stomatitis (mIAS), and the area under the curve (AUC) of mIAS-associated pain over an 8-week treatment period. A Fisher's exact test was used to compare the incidences while a Wilcoxon rank-sum test was used to compare the AUCs. In addition, we performed an exploratory analysis of the association of everolimus trough concentrations and toxicity using a Mann-Whitney U test. Due to slow accrual, this study closed after 39 patients were randomized (19 to upfront placebo and 20 to upfront dexamethasone). There were no significant differences between groups seen in either of the coprimary endpoints; furthermore, we found no association between whole blood everolimus trough concentrations and toxicity. Although limited by poor enrollment, the results of this study do not suggest that prophylactic dexamethasone mouthwash is superior to therapeutic dexamethasone mouthwash (initiated at the first sign of mouth pain) for reducing the incidence or severity of mIAS from everolimus.

The effectiveness of topical forms of dexamethasone in the treatment of oral lichen planus- A systematic review.

The goal of this systematic review was to assess the efficacy of dexamethasone compared to other treatments in oral lichen planus (OLP). The literature search used the following inclusion criteria: randomized controlled trials (RCT) comparing dexamethasone and other treatment strategies in patients with OLP. The outcome measures included relief of symptoms, decrement of erosive area size, and changes in quality of life. A computer and manual search was performed in Pubmed, Web of Science, and Cochrane Library up to January 31, 2021. The risk of bias was measured with the Revised Cochrane risk-of-bias tool for randomized trials. Eight trials with 131 study participants and 132 controls were identified. The following interventions were compared dexamethasone mouthwash, and 5% methylene blue-mediated photodynamic therapy, low-level laser therapy, amlexanox, clobetasol mouthwash, ketoconazole with amitriptyline, and thalidomide 1% paste. The therapeutic outcomes were more advantageous for dexamethasone in comparison with photodynamic therapy (PDT) (2 RCT) and low-level laser therapy (LLLT). Comparable effects were observed for dexamethasone, amlexanox, thalidomide, and PDT (1 RCT). Clobetasol showed more effective action than dexamethasone. Given the small sample sizes, heterogeneity and the few studies included, there is limited evidence to support the selection of treatment for OLP.

Clinical efficacy of a buccoadhesive paste from Fenugreek seeds (Trigonella foenum graecum L.) on recurrent aphthous stomatitis: in-vitro assessment of non-toxic concentration and pilot trial

ContextRecurrent aphthous stomatitis (RAS) is a highly prevalent oral lesion that is limited in many cases to symptomatic remedies. ObjectiveIn this work, a buccoadhesive paste was prepared from Fenugreek extract (Trigonella foenum graecum L.) and clinically evaluated on RAS patients. DesignThis study was a double blind randomized clinical trial. SettingThe study took place at Kerman University of Medical Sciences, Department of Oral Medicine, School of Dentistry. ParticipantsSCytotoxicity of fenugreek extract was studied on five cell lines using MTT and Neutral red assay. A buccoadhesive paste was formulated at non-toxic concentration. ixty patients randomly in two groups were treated with fenugreek buccoadhesive paste (FBP) and dexamethasone mouthwash respectively. The patients were followed for the intensity of pain, size of the lesion, erythema and exudate severity on 0, 4, 6, 10 days after the treatment. ResultsFrom the fourth day of the treatment, the size of the lesion and severity of pain was significantly improved in patients treated with FBP. On the sixth day of the intervention, the erythema level and the size of the ulcer significantly decreased (p < 0.05). ConclusionFBP could improve the most symptoms of RAS in comparison to the control due to the good adhesion of the paste to the surface of the ulcer and release the extract and forms a protective barrier against more mechanical irritations or infections.

Abstract PS11-11: Targeted safety events from a phase I/Ib study evaluating GDC-0077 alone and in combination with endocrine therapy (ET) ± palbociclib (palbo) in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract Background Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K) occur in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, is being developed as an anticancer agent. A phase I/Ib study of GDC-0077 alone and combined with other therapies is ongoing in pts with locally advanced or metastatic PIK3CAmut, HR+/HER2- mBC (NCT03006172). Targeted safety events are presented here. Methods Safety was assessed via NCI-CTCAE v4 for GDC-0077 administered alone (Arm A), with letrozole and palbo (Arm B), with letrozole (Arm C), with fulvestrant (Arm D), or with fulvestrant and palbo (Arm E, plus metformin in Arm F for pts with body mass index ≥ 30 and/or HbA1c ≥ 5.7%), in 28-day cycles until intolerable toxicity or disease progression. GDC-0077 was administered orally daily at 3, 6, 9, or 12 mg; letrozole, at 2.5 mg orally daily; palbo, at 125 mg orally 21/28 days; and fulvestrant, at 500 mg intramuscularly every 4 weeks. Targeted adverse events (AEs) included hyperglycemia, diarrhea, stomatitis (includes stomatitis, mucosal inflammation, mouth ulceration, glossitis, lip ulceration, palatal ulcer, and tongue ulceration), rash (includes rash, maculopapular rash, dermatitis acneiform, erythema, and erythematous rash), neutropenia (includes neutropenia and neutrophil count decreased), thrombocytopenia, and pneumonitis. Results As of clinical data cutoff (03/20/2020), 157 pts were enrolled and treated (Arm A: 20; Arm B: 33; Arm C: 37; Arm D: 39; Arm E: 13; Arm F: 15). Median cumulative dose intensity was 97.2% for GDC-0077, 90.6% for palbo, 99.9% for letrozole, and 100% for fulvestrant. Pneumonitis was reported in 2 pts, both in palbo-containing arms (grade 1 in Arm B; grade 2 in Arm F). Hyperglycemia required antihyperglycemic treatment in 69 pts (44%), and the most frequent agents used were metformin (39%; except Arm F where this was required as part of study treatment), empagliflozin (16%), and sitagliptin (15%). Fifteen pts (10%) required GDC-0077 dose reductions due to hyperglycemia. Stomatitis treatment was administered in 51 pts (32%), with dexamethasone mouthwash used most frequently (22%). Neutropenia and thrombocytopenia were managed with palbo dose reduction in 13 pts (21%) and 1 pt (2%), respectively. Overall, treatment-related AEs led to GDC-0077 discontinuation in 2 pts (1%) (grade 3 hyperglycemia in Arm B; grade 2 panniculitis in Arm F). Conclusion Targeted safety events with GDC-0077 alone and in combination ET ± palbo were manageable and required minimal GDC-0077 dose modifications or discontinuations. No unexpected safety events were reported in combination with palbo. A phase III study of GDC-0077 in combination with palbo and fulvestrant is enrolling currently (NCT04191499). Pts, n (%)Treatment-related AEsTreatment-related grade ≥ 3 AEsAll arms;All arms;N = 157N = 157Hyperglycemia98 (62)36 (23)Stomatitis (grouped terms)69 (44)2 (1)Diarrhea68 (43)0Rash (grouped terms)19 (12)1 (1)Palbo arms (B/E/F);Palbo arms (B/E/F);N = 61N = 61Neutropenia45 (74)36 (59)Stomatitis (grouped terms)41 (66)2 (3)Thrombocytopenia19 (31)4 (7) Citation Format: Mafalda Olivera, Komal Jhaveri, Dejan Juric, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Peter Schmid, Nicolas Turner, Andrea Varga, Guiyuan Lei, Stephanie Royer-Joo, Piia Thomas, Jennifer L Schutzman, Cristina Saura. Targeted safety events from a phase I/Ib study evaluating GDC-0077 alone and in combination with endocrine therapy (ET) ± palbociclib (palbo) in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-11.

SYSTEMIC PREDNISONE AS TREATMENT FOR EROSIVE ORAL LICHEN PLANUS: A CASE REPORT

Erosive lichen planus is a morbid variant of oral lichen planus. Chronic oral mucosal ulcerations accompanied by intense and disabling pain are some of its most characteristic manifestations. Here we present a case of a 52-year-old woman, nonsmoker, nondrinker, with history of hepatitis C treated 1 year ago. On extrabuccal examination, no changes were noted. Intra-oral examination revealed ulcers and erosions in the bilateral buccal mucosa, lip mucosa, lower lip vermilion, and gingiva, surrounded by white striae, all accompanied by intense pain. Biopsy was performed confirming the diagnosis of erosive lichen planus. As initial treatment, 0.5% dexamethasone mouthwash was prescribed, but there was no response. Therefore, systemic prednisone was administered orally in decreasing doses for 15 days. The lesions regressed to the aspect of normality of the mucosa, and the patient is under clinical follow-up without symptomatology for 2 years.

THE IMPORTANT ROLE OF ORAL MEDICINE SPECIALIST IN MANAGEMENT OF STEVENS-JOHNSON SYNDROME PATIENT

ABSTRACTIntroduction: Stevens-Johnson Syndrome (SJS) is an acute hypersensitivity reaction that manifests on the skin, oral mucosa, ocular, gastrointestinal, genital and anal area. It is also potentially life-threatening in concern of dehydration and infection. Oral mucosal lesions due to SJS resulted in a significant decrease of patient’s quality of life. When the oral mucosa involved, the intake of nutrients and fluids is disrupted contributing to electrolyte imbalance that aggravates dehydration. Moreover, oral mucosal lesions have become an entry point for infection. Purpose: This case report describes the important role of oral medicine specialists in the management of oral mucosal lesions in SJS patient. Review: A 26-year-old female patient was referred from the Department of Dermatology and Venereology with a diagnosis of SJS et causa suspected paracetamol and/or amoxycillin. The complaints comprised of pain on the lips and oral cavity, difficulty in mouth opening, and pain when swallowing. The management for oral lesions included: history taking, external and intra oral examinations, dexamethasone mouthwash, nystatin oral suspension, and sodium chloride (NaCl) 0.9% solution. The patient showed improvement in oral mucosal lesions within 3 weeks of treatment that was provided by oral medicine specialist and medical team collaboration. Conclusion: Based on this case report, the role of oral medicine specialist is very important as part of the management team for SJS patient. Oral medicine specialist can reduce morbidity that results from oral mucosal involvement. Collaboration with oral medicine specialist since the beginning of treatment is the key to success in SJS management. Keywords: Oral medicine specialist, Oral mucosal lesion, Stevens-Johnson Syndrome.

Abstract P1-19-46: A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer

Abstract Background: Dysregulation of the PI3K/AKT/mTOR signaling pathway occurs in solid tumor malignancies. GDC-0077 (G) is a potent p110α-selective, p110α-mutant degrading inhibitor with anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with endocrine therapies (ET) with or without a CDK4/6 inhibitor (i). An open-label, Phase I dose escalation study of Galone and in combination with ET and P is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the combinations of G and L with and without P in pts with PIK3CA-mutant HR+/HER2- breast cancer are presented herein. Methods: This study (NCT03006172) assesses the safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of G administered daily (QD) orally at 6 or 9 mg with L (G+L) or at 3, 6, or 9 mg in combination with P+L (G+P+L). L is administered QD orally at 2.5 mg. P is administered QD orally at 125 mg on Days 1-21 followed by 7 days off in 28-day cycles. For dose expansion, prior CDK4/6i was prohibited (G+P+L) and up to one prior metastatic chemotherapy allowed (G+L and G+P+L). Tumor and ctDNA samples (collected before and after 2 weeks of G) are profiled for relevant signaling and pharmacodynamic (PD) biomarkers. Results: As of 29 March 2019, 70 pts had enrolled (G+L: 37 pts [7 at 6 mg and 30 at 9 mg]; G+P+L: 33 pts [3 at 3 mg, 3 at 6 mg, and 27 at 9 mg]). Overall, 33 pts in G+L and 31 pts in G+P+L received ≥ 1 prior metastatic therapy; 70% and 21% of pts received prior CDK4/6i in G+L and G+P+L arms, respectively. No DLTs were reported in pts receiving either combination with G. In G+L, the most frequent treatment-related AEs (TRAEs) occurring in ≥10 (27%) pts included hyperglycemia (25 pts, 68%), nausea (14 pts, 38%), and diarrhea (10 pts, 27%). Grade ≥3 TRAEs in ≥2 (5%) pts included hyperglycemia (7 pts, 19%), and fatigue and hypokalemia (2 pts each, 5%). In G+P+L, the most frequent TRAEs occurring in ≥13 (41%) pts included neutropenia (25 pts, 78%), hyperglycemia (17 pts, 52%), anemia (17 pts, 52%), diarrhea (16 pts, 49%), and nausea and thrombocytopenia (13 pts each, 39%). Grade ≥3 TRAEs in ≥2 (6%) pts included neutropenia (21 pts, 64%), hyperglycemia (5 pts, 15%), lymphopenia (3 pts, 15%), and leukopenia and thrombocytopenia (2 pts each, 6%). Hyperglycemia was manageable with oral anti-hyperglycemic medication. Stomatitis (grouped term) occurred in 11 pts (30%) in G+L and 21 pts (64%) in G+P+L and responded to treatment with dexamethasone mouthwash. 46 pts discontinued treatment, mainly due to disease progression; one due to Grade 3 hyperglycemia in G+P+L (no discontinuation due to AE in G+L). Median G treatment duration: 5.7 months (range 0.2-14.5) in G+L and 9.7 months (range 1.3-23.1) in G+P+L, with a cumulative G dose intensity of 98% for both. In G+ L, PR was reported in 6 pts (16%), confirmed PR in 3 pts (8%) and CBR 35% (13 pts). In G+P+L, PR was reported in 14 pts (42%), confirmed PR in 12 pts (36%) and CBR 76% (25 pts). G PK parameters were similar to those observed as a single agent, and P and L showed exposures comparable with historical data, suggesting an absence of PK drug-drug interaction (DDI). Robust PD downregulation of PI3K pathway effectors (pAKT, pS6) was observed in available paired biopsies and PIK3CA mutant allele frequency decreased in ctDNA on-treatment in most patients. Conclusion: This Phase Ib study of GDC-0077 in combination with letrozole with and without pabocicilb demonstrated a manageable safety profile combining GDC-0077 at its single agent recommended Phase II dose of 9 mg with letrozole with and without palbociclib at standard doses, with no evidence for DDI, high GDC-0077 dose intensity, and promising preliminary anti-tumor activity. Citation Format: Komal Jhaveri, Kevin Kalinsky, Philippe Bedard, Andres Cervantes, Cristina Saura, Ian Krop, Erika Hamilton, Peter Schmid, Andrea Varga, Nick Turner, Antoine Italiano, Valentina Gambardella, Zachary Veitch, Mafalda Oliveira, Leslie Dickmann, Naoki Kotani, Amy Kapp, Katie Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer Schutzman, Dejan Juric. A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-46.

TREATMENT OF ORAL CHRONIC GRAFT-VS-HOST DISEASE WITH CLOBETASOL: CASE REPORT

Graft-vs-host disease (GVHD) is the main complication of allogeneic hematopoietic stem cells transplantation. A 29-year-old Brazilian man was diagnosed as having severe aplastic anemia and submitted to allogeneic HSCT in October 2013. He developed systemic chronic GVHD, including the oral cavity (lichenoid lesions in right and left buccal mucosa and labial hyperchromia and was treated with mycophenolate mofetil, tacrolimus, cyclosporine, and dexamethasone solution [mouthwash]). Upon stabilization of chronic GVHD in the oral cavity, the patient displayed gingival atrophy and erythema (12-21/33-42) on July 27, 2017. Dexamethasone mouthwash and tacrolimus ointment was unsuccessful. On November 11, 2017, the patient was instructed to use clobetasol gel 0.05% on individual tray 4 times/d/15 min. The total regression of gingival chronic GVHD was observed within 22 days. On January 1, 2018, the patient presented relapse of gingival erythema (12-21) with worsening of condition due to treatment discontinuation. We observed that clobetasol on individual tray was effective in this case.

Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer

BackgroundAlteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC.MethodsThe primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks).ResultsTwenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]).ConclusionEribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle.Trial registrationClinicalTrials.gov, NCT02120469. Registered 18 April 2014

Abstract CT107: Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Efficacy and safety results from phase II of the TRINITI-1 study

Abstract Background: Combining endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor significantly improves progression-free survival (PFS) over ET alone in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, optimal management of disease that progresses on this therapy is not established. In Phase 1 of the TRINITI-1 study (ClinicalTrials.gov identifier: NCT02732119), continuous ribociclib 300 mg/d + everolimus (EVE) 2.5 mg/d + exemestane (EXE) 25 mg/d, the recommended Phase 2 dose, resulted in 1 dose-limiting toxicity. Clinical benefit at week 24 was found in 3 of 6 patients whose disease had progressed on a CDK4/6 inhibitor. Here we report Phase 2 efficacy and safety in patients whose disease progressed on a CDK4/6 inhibitor. Methods: Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on ≤3 lines of therapy for ABC (1-3 lines of ET and ≤1 line of chemotherapy) and had measurable disease and/or lytic/mixed bone lesions were eligible. Progression on 1 CDK4/6 inhibitor, as the last therapy before enrollment, after ≥4 months of treatment for ABC was required. Dexamethasone mouthwash was required for the first 8 weeks. The primary objective of clinical benefit at 24 weeks in Phase 2 would be met if ≥9 of 42 patients had clinical benefit at 24 weeks. Secondary objectives included PFS, tumor response, safety, and tolerability. Results: Of 46 enrolled patients, 44 were evaluable; among 42 evaluable for efficacy, 6 had prior chemotherapy, 13 had ≥2 prior lines of therapy (median, 1 line), and 13 were on therapy on December 15, 2017. At week 24, 17 patients (40.5%) had clinical benefit by local assessment; the overall response rate was 7.1% (n=3; all had partial response at week 24). Median PFS was 8.8 months (95% CI, 1.9 months-not evaluable). In the safety set (n=44), there was 1 on-treatment death unrelated to study drug; 1 patient discontinued with Grade 4 hypophosphatemia. Common (≥25%) any-grade adverse events were neutropenia (68.2%), stomatitis (45.5%), fatigue (38.6%), nausea (34.1%), thrombocytopenia (34.1%), diarrhea (29.5%), and anemia (25.0%). Seven patients (15.9%) had Grade 1/2 pneumonitis, 23 (52.3%) had Grade 3/4 neutropenia, 2 (4.5%) had Grade 3/4 increased aspartate aminotransferase, and 1 (2.3%) had Grade 3/4 increased alanine aminotransferase. Febrile neutropenia, Grade 3/4 stomatitis or pneumonitis, and corrected QT interval (Fridericia's formula) &amp;gt;480 ms were not observed. Conclusion: TRINITI-1 is the first trial to demonstrate promising clinical benefit and tolerability of continuous ribociclib 300 mg/d, EVE 2.5 mg/d, and EXE 25 mg/d following progression on a CDK4/6 inhibitor, warranting further evaluation of this combination. Citation Format: Stacy Moulder, Megan Karuturi, Denise A. Yardley, Gail Shaw Wright, Sara Hurvitz, Rebecca Moroose, Tara Sanft, Cynthia Ma, Amelia Zelnak, Angela DeMichele, Amy Clark, Das Purkayastha, Alisha Khullar, Nicola Caria, Aditya Bardia. Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Efficacy and safety results from phase II of the TRINITI-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT107.

Efficacy of photodynamic therapy or low level laser therapy against steroid therapy in the treatment of erosive-atrophic oral lichen planus.

The efficacy of photodynamic therapy (PDT) or low level laser therapy (LLLT) in the treatment of oral lichen planus (OLP) is debatable. The aim of this study was to compare the effects of PDT, LLLT or topical corticosteroid application in the treatment of erosive-atrophic OLP. Forty-five adult patients with erosive-atrophic biopsy-proven OLP on the tongue or buccal mucosa (size ≤3 cm) were randomly divided into three groups. Group-1: patients receiving PDT topical application of 50 μl toluidine blue (1 mg/ml) with micropipette and after 10 min treated by laser irradiation using GaAlAs laser (630 nm, 10 mW/cm2, continuous wave, spot size: 1 cm2); Group-2: patients receiving LLLT using diode laser (630 nm, 10 mW, continuous wave, spot size: 1 cm2); and Group-3: patients receiving topical corticosteroid applications consisting of dexamethasone (0.5 mg in 5 ml water) mouthwash for 5 min. Demographic data, type, and severity of the lesions and pain were recorded before and after treatment and then at the 1 year follow-up. There was a significant difference in sign score changes before and after the treatment in the PDT group (p = 0.03), LLLT group (p = 0.04) and in the control group (p = 0.02). There was a statistically significant difference between group-1 (p = 0.001) and group-2 (p = 0.001) against group-3 before and after treatment. Mean amount of improvement in pain was significantly greater in the control group in comparison with the PDT and LLLT groups (p < 0.001). The efficacy index of the PDT group improved significantly more than the LLLT (p = 0.001) and corticosteroid groups (p = 0.001). Within the limits of the present RCT, it is indicated that PDT and LLLT are effective in the treatment of erosive-atrophic forms of OLP in adult patients. However, further comparative clinical trials are needed to obtain strong conclusions in this regard.

Comparing clinical effects of photodynamic therapy as a novel method with topical corticosteroid for treatment of Oral Lichen Planus

BackgroundOral lichen planus is an autoimmune disorder with several challenges in treatment. Photodynamic therapy has been proposed as a new treatment option for the disease. AimThe present study compared the clinical effects of photodynamic therapy to dexamethasone mouthwash in the treatment of oral lichen planus lesions. Materials and methodsIn this randomized clinical trial, 30 patients with oral lichen planus were included.15 patients were treated with 5% methylene blue mediated photodynamic therapy using Fotosan device for 30s (630nm wavelength and 7.2–14.4J/cm2 dose) for 4 sessions in the days 1, 4, 7, 14. In another group, the treatment was done on 15 patients by 0.5mg tab dexamethasone solution in 5cc water, rinsed 4 times in a day within two weeks. The sign score, symptoms scores (pain), clinical severity and treatment efficacy were measured at the days 15, 30, 60, 90 after beginning of the treatment. The results were subjected to Mann-whitney U test in both groups. ResultsNo significant difference existed between the two modalities regarding the treatment efficacy index, sign score, symptom score and clinical severity on the 15, 30, 60 and 90 post-treatment days. Decreases in patient’s symptoms were statistically significant in both groups. ConclusionPhotodynamic therapy was as effective as the dexamethasone mouth wash in the treatment of oral lichen planus. It could be used as a safe modality in the treatment of oral lichen planus lesions without identified side effects.

Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial

Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients). Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy. Novartis Pharmaceuticals Corporation.

Management of oral Graft versus Host Disease with topical agents: A systematic review.

BackgroundOral Graft-versus-Host Disease (oGvHD) is a common complication of haematopoietic stem cell transplantation. Choosing the right topical application to be used intra orally can be a challenge. Consequently, the aim of this work is to review the effectiveness and safety of topical agents currently used in the management of the inflammatory mucosal lesions encountered in oGVHD.Material and MethodsWe carried out electronic searches of publications up to May 2015 of the databases Pubmed, National Library of Medicine’s Medline, Embase and the Cochrane Central Register of Controlled Clinical trials to identify potentially relevant studies (keywords: “oral”, “graft”, “versus”, “host”, “disease” and “treatment”). The main inclusion criterion was the reported use of a topical agent which was not intentionally swallowed when used for the treatment of oGVHD. A 3-point grading system, described by the Swedish Council on Technology Assessment in Health Care and the Centre for Reviews and Dissemination, University of York, was used to rate the methodological quality of the papers.ResultsFrom the 902 entries identified in the search, 7 studies qualifying for inclusion were analysed. Overall, there is limited evidence with regards to the effectiveness of topical steroids for oGVHD. However, the studies showed some effect of Budesonide alone and when combined with dexamethasone. Topical tacrolimus also appears to have some effect and clobetasol propionate mouthwash had a significantly better clinical response than dexamethasone mouthwash in treating oGVHD.ConclusionsAs the number of clinical trials conducted is limited, there is little evidence to support the use of topical therapies to treat the inflammatory mucosal lesions found in oGVHD. High quality randomised control trials are needed in order to measure the effectiveness of any topical application for the treatment of the inflammatory mucosal lesions found in oGVHD. Key words:Oral, graft versus host disease, topical, therapy.

A Randomized Placebo-controlled Double Blind Clinical Trial of Quercetin for Treatment of Oral Lichen Planus.

Background and aims. Standard treatment of oral lichen planus (OLP) includes topical or systemic corticosteroids that have many adverse effects. A trend toward alternative natural or herbal drugs has attended recently. This study was conducted to evaluate the effect of quercetin in treatment of erosive-atrophic OLP.Materials and methods. Thirty patients participated in this randomized clinical trial from April 2010 to June 2010 (Trial Registration Number: NCT01375101). Patients were randomly allocated in two groups. Both groups received the standard treatment (dexamethasone mouthwash and nystatin suspension). Experimental group received oral 250 mg quercetin hydrate capsules (bid) and the control group received placebo capsules. The pain and severity of the lesions were recorded at the initial visit and the follow-ups. All recorded data were analyzed with chi-square, Mann-Whitney, t-test, Wilcoxon and Friedman tests using SPSS 11.5.Results. There were no significant differences between the two groups in severity of the lesions and pain in the follow-ups.According to the Friedman test, there was a significant reduction in pain (P = 0.01) and severity indices (P = 0.00) in the case group. These differences were not observed in the control group(P = 0.26,SI; and P = 0.86, PI). No adverse effect of quercetin was reported.Conclusion. According to the results, no significant therapeutic effect can be considered for quercetin in treatment of OLP.

Effect of cedar honey in the treatment of oral lichen planus.

Oral Lichen Planus (OLP) is a chronic mucocutaneous disease with an immunological etiology. This study was conducted to evaluate the effect of cedar honey in the treatment of erosive- atrophic OLP. Thirty patients with a confirmed clinical and histopathologic diagnosis of OLP participated in this randomized clinical trial in Mashhad Dental School. Patients were randomly allocated into one of two groups. Both groups received standard OLP treatment (dexamethasone mouthwash 0.5 mg three times daily and fluconazole capsule 100 mg daily). The intervention group received cedar honey (20 ml three times daily, via a swish and swallow technique) in addition to standard treatment. The patients were followed for 4 weeks. The pain and severity of the lesions were recorded at the initial visit and follow ups. All recorded data were analyzed using the chi-square test, T-test, and analysis of variance (ANOVA) using SPSS version 11.5. A p-value less than 0.05 was considered significant. Both groups had a marked reduction in pain, size of erosive area, and atrophic lesions, particularly in the first follow-up period, but there was no significant difference between the two groups (P>0.05). Honey was effective in the healing of ulcerative lesions (average recovery in the experimental group was 69% while the average relief of ulcerative lesion in the control group was 50%), but the difference was not significant (P=0.896). No significant difference was found in the treatment of atrophic and erosive lesions of OLP through use of honey as an alternative treatment. However, this approach may be effective in managing ulcerative lesions of OLP; although more research with a larger sample size is necessary.