Maculopapular Research Articles

Dengue Fever Manifesting as Haemorrhagic Bullae: A Rare Presentation

Abstract Dengue fever, a viral disease transmitted by Aedes mosquitoes, is a global health problem affecting millions of people each year. It is prevalent in tropical and subtropical areas, with epidemic potential due to climate change and increased travel. The disease commonly presents with cutaneous symptoms such as erythema, maculopapular rash and minor haemorrhagic lesions. This case is notable for the unusual presentation of haemorrhagic bullae, resembling drug eruption or autoimmune bullous disease. In the field of dermatology, tropical diseases like dengue have rarely been discussed. However, the recent increase in cases in Southeast Asia highlights the need for dermatologists to become familiar with dengue, as it often presents with diverse skin rashes. Herein, we report an unusual case of dengue fever presenting with haemorrhagic bullae.

Dermatologic manifestations of patients with severe and non-severe COVID-19 infection: A cross-sectional study

Introduction: Since the emergence of COVID-19 in late 2019, multiple concerns have been raised regarding the unknown nature of the disease, including dermatologic complications. In this study, we discussed dermatologic manifestations of patients with COVID-19 infection who visited our clinic. Methods: Eighty- six patients were involved based on our inclusion and exclusion criteria (50 female and 36 male). All patients with definite diagnosis of COVID-19 who were referred to our dermatologic clinic were enrolled in this cross-sectional study. Only lesions which occurred 1 week prior to or 3 months after first COVID-19 symptoms were included. The photographs of all lesions were independently reviewed by four experienced dermatologists and an infectious disease specialist to reach the objectives stated above. Qualitative data presented as frequency (%) and compared using chi-squared or Fisher’s exact test, and quantitative data presented as mean±SD or median (IQR) based on normality, with P value≤0.05 considered statistically significant. Results: Eighty- six patients were enrolled in the study (mean±SD age=36.95±17.78). Eighteen specific types of dermatologic complications were seen. The most common lesions included maculopapular rash and scalp hair loss. The only lesions with a statistically significant difference regarding COVID-19 symptom onset time were maculopapular rash, telogen effluvium, and papular urticaria. The only lesions with statistically significant difference regarding COVID-19 severity were maculopapular rash, telogen effluvium, and urticaria. Conclusion: Our study revealed that a wide range of skin lesions may occur in patients with COVID-19. We found a statistically significant relation between disease severity and certain dermatologic manifestations.

Mayaro Virus: An Emerging Alphavirus in the Americas.

Mayaro virus (MAYV) is an arbovirus first isolated in Trinidad and Tobago in 1954. MAYV is the causative agent of Mayaro fever, which is characterised by high fever, maculopapular rash, myalgia and arthralgia. The potential for chronic arthralgia is of particular clinical concern. Currently, MAYV outbreaks are restricted to South and Central America, with some cases reported in Africa as well as several imported cases in Europe. However, in recent years, MAYV has become a growing global concern due to its potential to emerge into urban transmission cycles. Challenges faced with diagnostics, as well as a lack of specific antivirals or licensed vaccines further exacerbate the potential global health threat posed by MAYV. In this review, we discuss this emerging arboviral threat with a particular focus on the current treatment and vaccine development efforts. Overall, MAYV remains a neglected arbovirus due to its limited area of transmission. However, with the potential of its urbanisation and expanding circulation, the threat MAYV poses to global health cannot be overlooked. Further research into the improvement of current diagnostics, as well as the development of efficacious antivirals and vaccines will be crucial to help prevent and manage potential MAYV outbreaks.

Granulomatous Folliculotropic Secondary Syphilis: An Unusual Histopathological Clue.

Syphilis is a sexually transmitted disease that can present a wide variety of clinical and histopathological manifestations. We present the case of a 75-year-old patient with a persistent maculopapular rash on the trunk and extremities, in which the biopsy showed an exclusively perifollicular granulomatous infiltrate. In the immunohistochemical staining with anti-Treponema pallidum antibodies, spirochetes scattered within the perifollicular inflammatory infiltrate were identified. These findings together with the serological analysis allowed the diagnosis of secondary syphilis. Folliculotropic nonalopecic syphilis is rare, and the pathogenic mechanisms that cause this specific tropism are unknown. On the other hand, granulomatous inflammation is a pattern typically described in tertiary syphilis but also occasionally found in secondary syphilis. We present a case of secondary syphilis with the combination of both histopathological findings, an uncommon constellation for dermatopathologists to consider.

Bullous Drug Eruption.

A 63-year-old woman presented at our emergency department with a disseminated dermatosis that developed after undergoing a cardiac catheterization procedure. Her past medical history included an end-stage renal disease undergoing hemodialysis. Clinical examination revealed erosions and hemorrhagic crusts located on her lips and along the arteriovenous fistula. Additionally, we observed five hyperpigmented macules on her left hand's dorsum and palm and multiple hypopigmented macules in the genital area. Upon medical record review, we discovered the occurrence of prior bullous eruptions following contrast administration. A fixed drug eruption (FDE) due to radiocontrast was diagnosed based on clinical history, clinical examination, eruption timeframe, and positive drug provocation test. Intravenous contrast media reactions can be immediate or delayed, with delayed hypersensitivity reactions (DHR) occurring one hour to seven days post-administration. DHRs often present as maculopapular rashes. FDEs are rare. Skin tests are used to identify culprit agents. Ideally, intradermal tests, with delayed readings, and patch tests are combined for optimal sensitivity. Despite lacking standardized protocols, premedication with corticosteroids may mitigate reaction severity.

Prospective Analysis of Cutaneous Adverse Drug Reactions Encountered in a Tertiary Care Hospital.

Adverse drug reactions (ADRs), including cutaneous adverse drug reactions (CADRs), are significant global health concernswith India among the top affected countries. CADRs represent a significant concern in healthcare, impacting the skin, its appendagesand mucous membranes ranging from mild rashes to severe, life-threatening conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis. Self-medication with over-the-counter drugs is a notable public health issue linked to CADRs. Clinical trials often miss long-term and rare CADRsmaking early detection and monitoring crucial. This study aims to evaluate CADRs by assessing their causality, severityand preventability; determining onset lag time; identifying morphological patterns; and investigating associations with different drug classes. It also explores the links between self-medication and CADRs and analyses related outcomes. This research addresses gaps in understanding CADRs' epidemiology, impact and managementproviding valuable insights for healthcare practitioners. A 12-month prospective observational study conducted at a tertiary care hospital involved dermatology patients from both outpatient and inpatient units. Inclusion criteria comprised patients diagnosed with CADRs by physicians in the outpatient department (OPD) (active surveillance) and reported cases to pharmacovigilance unit (passive surveillance)while those unwilling to provide written consent were excluded. The majority (44.25%) of the patients were aged 18-39 years. Maculopapular rash (53.98%) and urticarial rash (9.73%) were the most common CADR types. Anti-bacterials (42.63%) were the primary suspected drug class. Serious CADRs were predominant (74.34%)with 1.77% resulting in fatalities. Severity was moderate in 79.65% and mild in 17.7% of the cases. Preventability was low (5.31%)with three CADRs attributed to self-medication. Recovery was seen in 46.9% of the patientswith 42.48% still in recovery at discharge and a mortality rate of 1.77% due to Stevens-Johnson syndrome. A comprehensive pharmacovigilance system for continuous monitoring of patients' health status can lead to opportunities to reduce the CADRs, lower drug-related morbidityand rationalize drug therapy.

Genetic analysis of a child with Dyschromatosis symmetrica hereditaria

To investigate the clinical and genetic features of a child with Dyschromatosis symmetrica hereditaria (DSH) and variant of the ADAR1 gene. A child who was admitted to the Department of Dermatology of the First Affiliated Hospital of Zhengzhou University in June 2020 due to irregular pigmented maculopapular rash on the dorsum of hands was selected as the study subject. Whole exome sequencing (WES) was carried out for the child and his similarly affected father, and Sanger sequencing was used to verify the candidate variant. SWISS-MODEL was used to predict the secondary and tertiary structures of the wild-type and mutant ADAR1 proteins. The child, a 13-year-old boy, had symmetrical hyperpigmented and depigmented spots on the back of his hands and was clinically diagnosed with DSH. WES and Sanger sequencing results showed that he and his father had both harbored a heterozygous c.2858dup (p.T954Dfs*20) truncating variant in exon 10 of the ADAR1 gene. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was predicted as pathogenic (PVS1+PM2_Supporting+PM1+PP3). The c.2858dup (p.T954Dfs*20) variant of the ADAR1 gene probably underlay the DSH in this pedigree.

“A study on prevalence of measles at tertiary care hospital and study on demographic profile of patients infected with measles virus”

Measles virus belonging to the genus Morbillivirus in the family Paramyxoviridae, transmitted by aerosol and characterized by fever, respiratory symptoms, redness of eyes & maculopapular rash. Material & methods: Children’s 0-15 years of age with suspected case of measles symptoms like fever, cough, redness of eyes & maculopapular rash attending at Hospital which included in the study. Serum samples were screened for measlesIgM by ELISA method.

Skin Rash with Acute Respiratory Distress Syndrome in Chronic Miliary Tuberculosis: The Role of HRCT Thorax and Bronchoscopy as Diagnostic Tools

Pulmonary tuberculosis (TB) is a leading cause of mortality and morbidity in India, presenting with diverse clinical and radiological manifestations such as consolidation, cavitation, lymphadenopathy, pleural effusion, miliary TB, and endobronchial TB. While acute miliary TB presenting as Acute respiratory distress syndrome (ARDS) is documented, the association with a skin rash mimicking viral exanthematous fever is not. This case report describes the case of a 41-year-old male patient with acute dyspnea, a maculopapular rash, and lung infiltrates on chest radiograph, initially diagnosed with acute hypoxic respiratory failure and later confirmed as ARDS. High-resolution computed tomography (HRCT) thorax revealed consolidation with nodules and a characteristic butterfly pattern sparing the apices and bases. Bronchoscopy confirmed TB etiology through MTB genome in BAL samples. The patient improved significantly with intravenous antibiotics, steroids, and HFNC, leading to a documented cure after 6 months of anti-tuberculosis treatment. This report highlights the importance of considering TB in cases with nodular consolidation and positive limiting signs and recommends ICU bronchoscopy as a reliable diagnostic tool. The Kigali modification for ARDS definition was instrumental in managing this case. Use of Kigali modification for defining ARDS in resource limited setting guided management in our case.

AZITHROMYCIN-INDUCED HYPERSENSITIVITY AND COVID-19: A CASE REPORT

An adverse drug reaction is called drug hypersensitivity syndrome. However, experts regard macrolide allergies to be infrequent. Moreover, this group of antibiotics is considered relatively safe. Although azithromycin is prescribed in COVID-19 patients due to the positive observed effects, hypersensitivity syndrome from this agent has rarely been reported. The case study discusses a 30-year-old man, who was diagnosed with coronavirus disease 2019 and exhibited fever (39.1°C), diffuse maculopapular rash, shortness of breath, wheezing, swelling, itching, pain, subconjunctival hemorrhage, eosinophilia (8.9% of 10.2×103/μL leukocytes), and elevated aminotransferase level following treatment with azithromycin. The Naranjo algorithm classified this case in the “definite” category. Therefore, due to the high prevalence of COVID-19 and increased administration of azithromycin, physicians should be made aware of the potential for unusual toxicity associated with azithromycin, which may become more prevalent as its use continues to expand in the future.

Long chikungunya? An overview to immunopathology of persistent arthralgia

Chikungunya fever (CF) is caused by an arbovirus whose manifestations are extremely diverse, and it has evolved with significant severity in recent years. The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses. Generally, fever starts abruptly and reaches high levels, followed by severe polyarthralgia and myalgia, as well as an erythematous or petechial maculopapular rash, varying in severity and extent. Around 40% to 60% of affected individuals report persistent arthralgia, which can last from months to years. The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system. The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Β ligand and bone resorption. This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages, leading to local infiltration of CD4+ T cells, which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines. The term "long chikungunya" was used in this review to refer to persistent arthralgia since, due to its manifestation over long periods after the end of the viral infection, this clinical condition seems to be characterized more as a sequel than as a symptom, given that there is no active infection involved.

Capmatinib plus nazartinib in patients with EGFR-mutated non–small cell lung cancer

PurposeThis phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC). MethodsIn phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200–400 mg bid plus nazartinib 50–150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1–3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0–2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M−; any MET); group 4 (with food; 0–2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1–3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. ResultsThe RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET− (n = 42), T790M+ (n = 29), and T790M− (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). ConclusionCapmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. Clinical trial registrationClinicalTrials.gov NCT02335944

LGG-55. DIFFERENTIAL TOXICITY PROFILE OF INDIVIDUAL MEK INHIBITORS: A MULTI-INSTITUTION RETROSPECTIVE REVIEW

Abstract BACKGROUND Most pediatric low-grade gliomas (pLGGs) are driven by molecular aberrations in the mitogen-activated protein kinase pathway (MAPK), which can be targeted by novel agents such as MEK inhibitors (MEKi.) However, MEKi use is accompanied by a varied side effect profile, with the most severe dose-limiting effects involving dermatologic, cardiac, and ophthalmic toxicities. METHODS Multi-institutional retrospective chart review of patients less than 25 years of age who underwent MEKi monotherapy between 2015-2022 was conducted. Data was collected from 4 sites, including Connecticut Children’s, St. Louis Children’s Hospital, Cardinal Glennon Children’s Hospital, and Children’s Hospital of Philadelphia. RESULTS Ninety-six patients were included in the analysis; 54 (56.4%) with brain tumors and 56 (58.3%) with germline mutation in NF-1. Forty-nine (51%) received trametinib, 42 (43.8%) selumetinib, 5 (5%) binimetinib. Of 42 patients with skin toxicity data available, 35 (83%) had cutaneous toxicity, with the most prevalent being acneiform rash (40.0%), followed by maculopapular rash (28.6%) and eczematous dermatitis (11.4%). The mean number of cutaneous skin toxicities was 2.4 (trametinib group = 2.2, selumetinib group = 2.6). Eighteen of 96 (18.8%) patients experienced cardiac toxicity, of which 11 (61.1%), experienced reduction in left ventricular ejection fraction (6 trametinib, 5 selumetinib), 4 (22.2%) developed pericardial effusions. 10 of 96 (10.4%) patients experienced ophthalmic toxicities, most commonly blurred vision (30.0%). Other toxicities included elevated CK (36, 37.5%), anemia (32, 33.3%), and eosinophilia (17, 17.7%). CONCLUSION There was not an observable clinically relevant difference in toxicities between MEKi, with skin toxicity the most prevalent. The prevalence of cardiac toxicity in the patient cohort reinforces the need for appropriate monitoring via echocardiography. MEKi remain an excellent option for therapy for LGG but with the need for continued supportive care and monitoring.

Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

Exfoliated dermatitis and hepatitis to first line Anti-Tubercular Therapy with treatment of Drug-Sensitive Tuberculosis with second line Anti-Tubercular Therapy: a roller coaster ride

The Adverse Drug Reactions (ADRSs) to Anti-Tubercular Therapy (ATT) have been reported from 8% to 85% worldwide, while the prevalence of ADRSs to 1st line ATT from India reported 2.3% to 17%, with more during the intensive phase and daily regime. However, cutaneous ADRSs related to ATT are less commonly seen. Common cutaneous ADRSs are maculopapular rash, urticarial, erythema multiforme, exfoliative dermatitis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Among the 1st line ATT, pyrazinamide is the most common cause at 2.38%, and isoniazid is reported the least at 0.98%. Exfoliated dermatitis is rarely seen with 1st line ATT therapy limited to some case reports and case series.

Safety results from the phase 3 MajesTEC-7 study in patients (pts) with transplant ineligible/not intended newly diagnosed multiple myeloma (NDMM).

7506 Background: Despite recent advances in the treatment (tx) of transplant ineligible/not intended NDMM, most pts still relapse and require alternative txs, highlighting a need for new frontline tx options with new mechanisms of action to improve pt outcomes. Teclistamab (tec) demonstrated rapid, deep, and durable responses in the MajesTEC-1 trial (NCT03145181/NCT04557098). Preliminary data from the MajesTEC-2 trial (NCT04722146) demonstrated that tec, daratumumab (dara), and lenalidomide (len) combination (tec + DR) is tolerable, with promising efficacy in pts with relapsed/refractory MM and NDMM. The phase 3 MajesTEC-7 (NCT05552222) study will compare tec + DR vs DR + dexamethasone (dex) in pts with NDMM who are ineligible/not intended for ASCT as initial tx. We report the results of the first safety run-in (SRI) from MajesTEC-7. Methods: Eligible patients were aged ≥18 yrs with NDMM and ineligible/not intended for ASCT as initial tx, with measurable disease and an ECOG performance status (PS) score 0–2. Pts in the SRI received tec (step-up dose [cycle 1], QW [cycle 2], Q2W [cycle 3–6], and Q4W [cycle 7+]) + DR (as SOC) until progression, unacceptable toxicity, or death. Response assessments were based on IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Prophylactic immunoglobulin replacement was highly recommended. Results: As of Nov 27, 2023, 26 pts had received tec + DR (median, 11 cycles; range, 2–14) and 24 pts (92.3%) remained on tx. Median follow-up was 10.2 mo (range, 2–12). At baseline, median age was 72.5 yrs, 11.5% had an ECOG PS score of 2, and 15.4% had ≥1 soft-tissue plasmacytoma. 4 pts (15.4%) deferred transplant. Treatment-emergent AEs (TEAEs) occurred in 100% of pts (grade [gr] 3/4, 22 pts [84.6%]). Infections occurred in 25 pts (96.2%; gr 3/4, 8 pts [30.8%]). CRS occurred in 16 pts (61.5%; all gr 1). ICANS occurred in 1 pt (gr 1). Gr 3/4 TEAEs occurring in ≥3 pts were neutropenia (13 [50%]), febrile neutropenia (5 [19.2%]), thrombocytopenia (4 [15.4%]), COVID-19 (3 [11.5%]), maculo-papular rash (3 [11.5%]), and hypertension (3 [11.5%]). 1 pt discontinued tec + DR due to withdrawal of consent. 2 discontinued len due to TEAEs (gr 3 maculo-papular rash and gr 4 neutropenia). There was 1 death due to a TEAE in cycle 3 (pneumonia influenza). Overall response rate was 92.3% (complete response or better, 73.1%; very good partial response or better, 92.3%). Conclusions: These results from the first SRI of MajesTEC-7 demonstrate a manageable safety profile with early efficacy of tec + DR in NDMM. Two additional SRIs are ongoing investigating tec (less frequent dosing) + DR and talquetamab + DR. Clinical trial information: NCT05552222 .

Phase 1 trial of TU2218, TGFβ-RI and VEGF-R2 dual inhibitor in monotherapy and combination with pembrolizumab in patients with advanced solid tumors.

2613 Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance may emerge in some of the patients treated. VEGF and TGF-β pathways play an important role in the development and function of the tumor-microenvironment (TME), contributing to be the immunosuppressive. TU2218 is a highly potent, orally available dual inhibitor against TGFβ type I receptor (ALK5) and VEGFR2. This was a first-in-human study to investigate the safety and tolerability of TU2218 monotherapy and combination therapy with pembrolizumab. Methods: This non-randomized, open-label, multinational, multicenter study evaluated the safety, tolerability, PK, and preliminary efficacy of TU2218 alone and combination with pembrolizumab to determine the Recommended Phase 2 Dose of the Combination (RP2DC) in advanced solid tumors. Eligible patients were ≥ 18 years of age, ECOG performance status of 0 or 1 and had measurable lesion per RECIST 1.1. Part A of monotherapy was sequentially escalated to 6 dose levels of TU2218 ranging from 30 to 270 mg/day on a 2 weeks-on/1 week-off regimen using a BOIN design. In part B, patients received TU2218 doses of 105, 150 and 195 mg/day on a 2 weeks-on/1 week-off cycle in combination with pembrolizumab 200mg once every 3 weeks. Dose escalation followed a 3+3 design with a DLT evaluation period. Results: In the TU2218 monotherapy dosed BID (n=22), no Grade 3 or higher treatment related AE was reported, while all Grade 2 TRAEs were tolerable. Systemic exposure to TU2218 increased in a dose dependent manner. Following seven days of administration, TU2218 demonstrated reductions in PD markers and a correlation was observed between TU2218 exposure and the decrease of PD markers, particularly TGF-β1 (-16.5%) and CTGF (-45.4%) blood levels in groups of TU2218 Cmax ≥ 1.0 μM. Patients (n=12) received TU2218 at doses levels of 105 to 195mg/day in combination with pembrolizumab 200mg once every 3 weeks. The most frequently observed TRAE was pruritus (25%, n=3) and one patient experienced Grade 3 TRAE with maculo-papular rash (8.3%, n=1). No DLT was observed during the dose escalation and the MTD was not identified. The best ORR in the combination cohort demonstrated PR at 8.3% (n=1), SD 50% (n=6) and PD at 33% (n=4). The dose level at 195mg/day of TU2218 in combination with pembrolizumab was safe and tolerable. Conclusions: TU2218, a first-in-class oral dual inhibitor against TGFβRI and VEGFR2 was well-tolerated in the monotherapy and in the combination therapy with pembrolizumab. The RP2DC was established for subsequent trials in specific cancer types. Clinical trial information: Phase 1a: NCT05204862 / Phase 1b: NCT05784688 .

Efficacy from the phase 1 study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with head and neck squamous cell carcinoma.

6042 Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) have limited treatment options after progression on first-line immunotherapy with or without platinum-based chemotherapy. Taxanes in this setting have historically demonstrated response rates around 14-27%. FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. This allows the drug to remain in solution until it can enter a cancer cell and preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel. In the phase I study of FID, we determined 125 mg/m2 as the recommended phase 2 dose. Here we present updated safety and efficacy data with emphasis on pts with HNSCC. Methods: The study evaluated the safety, PK, and preliminary efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a 3+3 dose escalation. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and < 3 prior lines of cytotoxic therapy. Results: 46 patients were enrolled, of which 9 had HNSCC (2 nasopharynx, 2 sinonasal, 3 oropharynx, 1 oral cavity, and 1 occult primary). Median age (range) was 60 (53-75). ECOG PS was 1 in all HNSCC pts. Median number of prior therapies was 3 (1-5) and all had received prior immune checkpoint inhibitor. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts included rash (72%), alopecia (52%), leukopenia (46%), pruritus (43%), neutropenia (41%), anemia (37%), fatigue (37%), nausea (28%), and anorexia (28%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (35%), neutropenia (20%), leukopenia (20%), anemia (17%), lymphopenia (7%), and febrile neutropenia (4%). No pts experienced > grade 2 peripheral sensory neuropathy; 20% experienced grade 1-2. Across all solid tumors, the overall response rate (ORR) was 17%. In patients with HNSCC, 5 (56%) had a partial response, 2 (22%) had stable disease, and 2 (22%) had PD. Three out of 5 HNSCC patients previously treated with a taxane achieved a partial response. Median duration of treatment was 4 months (1-15). Conclusions: FID demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated HNSCC pts across different primary tumor sites, with an ORR 56%, including those with prior taxane exposure. A phase 2 study of FID with cetuximab in pts with HNSCC is planned to begin enrollment in 2024. Clinical trial information: NCT03537690 .

A phase 2 clinical trial of regorafenib in patients with advanced pretreated melanoma (RegoMel).

9518 Background: A majority of advanced melanoma patients (pts) will eventually progress despite treatment with PD-(L)1/CTLA-4/LAG-3 immune checkpoint- and BRAF-/MEK-inhibitors (BRAF-/MEKi; restricted to BRAFV600-mutant pts). Retrospective case observations indicate activity of regorafenib (REGO) in this setting (1). Methods: This single center, prospective, two-stage, phase 2 clinical trial, investigates REGO 80 mg QD (continuous dosing) in pts with advanced melanoma refractory to standard of care treatment. Objective response rate (ORR, by RECIST v1.1) served as the primary endpoint. The sample size (n=16) was determined according to a Simon’s two-stage minimax statistical design; the trial is considered positive if 3 or more responses are observed. Response assessments are performed every 6 weeks (q6w) during the first 24w, and q12w thereafter. Secondary endpoints are safety, progression free survival (PFS) and overall survival (OS). REGO treatment beyond first progression was permitted if considered to be of potential clinical benefit. Database lock was on Jan 9th, 2024. Results: From Oct 2022 to Sep 2023, 16 pts were enrolled (9 male, med age 61y; AJCC stage IIIC: 1; IV-M1a: 1; -M1c: 12, -M1d: 2, ECOG PS 0-1: 100%). Oncogenic driver mutations were identified in BRAFV600: 7-, KIT: 3-, NF1: 3-, NRASQ61K: 2-, RAF fusion: 1 pt. The ORR was 31% (: 5 partial responses (PR) - 4 confirmed in 3 KIT-,and 1 BRAFV600 -mut pt; and 1 unconfirmed in a BRAFV600-mut pt). One KIT-mut pt had previously progressed on imatinib. The median duration of response (DoR) was 29.7w (range 12-44). The disease control rate (DCR) was 56%. The median time on REGO monotherapy was 12.3w [95% CI 2.3-22.3], treatment is ongoing in 3 pts. At first progression, 6 BRAFV600-mut pts continued REGO in association with BRAF-/MEKi, in 5 response evaluable pts there is an ORR of 40% (2 PR with DoR of 24w and 30w) and DCR of 80%. At database lock, 11 pts were alive with a median follow up of 48.4w (range 24-63), 13 pts have progressed on REGO monotherapy (median PFS 11.9w [95% CI 3.5-20.3]; median OS was not reached). There were no grade ≥ 4 treatment related adverse events (TRAE); 56% of pts had at least one grade 3 TRAE, including hypertension (n=3) and maculo-papular rash (n=2). There was one toxicity-related REGO discontinuation. Conclusions: This phase 2 clinical trial on REGO monotherapy in advanced pretreated melanoma patients met its primary endpoint and demonstrated significant anti-tumor activity in KIT-mutant melanoma patients. In BRAFV600-mutant melanoma, continuation of REGO in combination with BRAF-/MEK-inhibitors demonstrated promising activity in patients who previously progressed on BRAF-/MEK-inhibitors for which further prospective investigation is ongoing. 1. Dirven I. et al. ESMO Meeting 2023. Clinical trial information: NCT05370807 .

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).

4140 Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]