Increased Creatine Phosphokinase Research Articles

Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Abstract Background The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy. Methods This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization. Results Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, > 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE >= Grade 4 were reported. No patient discontinued treatment due to TEAE. Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study. Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-08.

Carbon monoxide poisoning manifesting with rhabdomyolysis, Takotsubo syndrome, and skin lesion: A case report

Carbon monoxide (CO) poisoning is characterized by non-specific and protean clinical manifestations, exhibiting a highly variable presentation. We present a case of an 83-year-old female Alzheimer’s patient, a non-smoker, who was found unconscious in her wheelchair by her caregiver at home. The heating in the apartment was powered by liquefied petroleum gas. On admission to the emergency department, her vital signs were normal, but she was unconscious and slightly dyspneic. The examination revealed red-colored skin lesions in the submammary area, where the wheelchair safety belt was firmly fastened. The rest of the physical examination results were unremarkable. The carboxyhemoglobin level was 23%, and there was an increase in creatine phosphokinase and troponin I levels. On the 2nd day of hospitalization in the emergency ward, the electrocardiogram revealed negative T waves in the V1–V6 leads, while the bedside echocardiogram revealed apical ballooning of the left ventricle. The myocardial perfusion examination yielded a negative result for myocardial ischemia. In the management of patients with CO poisoning, it is important for emergency physicians to assess the presence of multiple organ and tissue disorders. Consequently, the patient was diagnosed with CO poisoning with skin, skeletal, and cardiac muscle involvement.

Long-term efficacy and safety of baricitinib in patients with severealopecia areata: 104-week results from BRAVE-AA1 and BRAVE-AA2.

Efficacy of the Janus kinase (JAK) inhibitor baricitinib for severe alopecia areata (AA) continuously increased over 52 weeks in two Phase 3 trials. There are limited long-term data on JAK inhibitors in AA. To evaluate efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy. Integrated data from the BRAVE-AA1 and BRAVE-AA2 Phase 3 trials included adults with Severity of Alopecia Tool (SALT) scores ≥50 (≥50% scalp hair loss) randomized to and continuously treated with 2-mg or 4-mg baricitinib through Week 104. Patients who qualified to remain on continuous treatment included subjects who achieved SALT score ≤20 at Week 52 (Week-52 responders; 2-mg: N = 65; 4-mg: N = 129) and baricitinib 4-mg-treated patients who had SALT score >20 at Week 52 but achieved SALT score ≤20 at prior visit(s) and/or had significant improvement in eyebrow or eyelash hair growth relative to baseline by Week 52 (Week-52 mixed responders; N = 110). Week-104 outcomes included the proportion of patients achieving SALT score ≤20 (≤20% scalp hair loss). Data were censored after treatment discontinuation. Among baricitinib 4-mg-treated and baricitinib 2-mg-treated Week-52 responders, 90.7% and 89.2%, respectively, maintained SALT score ≤20 at Week 104. Among Week-52 mixed responders, 39.1% reached SALT score ≤20 by Week 104. Continued improvement in eyebrow and eyelash regrowth was observed across groups. The most frequent treatment-emergent adverse events were COVID-19, upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection and creatine phosphokinase increase. Baricitinib demonstrated a high level of maintenance of efficacy over 104 weeks in patients with severe AA. Efficacy increased in Week-52 mixed responders, illustrating that long-term treatment is necessary to observe maximum benefit in some patients. No new safety signals were observed.

Рабдомиолиз — редкое внелегочное проявление внебольничной пневмонии, вызванной Mycoplasma pneumonia

Aim. To present a clinical case of a 19-year-old patient with community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae, which was complicated by a rare extrapulmonary manifestation in the form of rhabdomyolysis. Key points. The clinical case demonstrates a variant of mycoplasma CAP in an adult patient. M. pneumoniae infection was confirmed by a positive PCR test. Characteristic is contact with a patient with mycoplasma CAP in an infectious focus, a flu-like onset of the disease. Unlike most mild mycoplasma infections with a minimally expressed clinical picture and inflammatory response, the patient had a long period of febrile temperature and severe intoxication, significant laboratory changes and bilateral polysegmental lung damage. The development of signs of rhabdomyolysis (myalgia, increased creatine phosphokinase (CPK) to 2066 U/L, myoglobinuria) in the acute period of the disease is a rare extrapulmonary manifestation of mycoplasma CAP in adults, dangerous for the development of acute renal failure (ARF). Conclusion. The patient's young age, timely initiation of hydration, and antibacterial therapy aimed at M. pneumoniae made it possible to prevent the development of acute renal failure due to rhabdomyolysis. An increase in CPK, in the absence of other explanations for this phenomenon, should include mycoplasma CAP in the differential diagnosis of rhabdomyolysis. Keywords: community-acquired pneumonia, Mycoplasma pneumoniae, creatine phosphokinase, rhabdomyolysis.

Опыт применения высокопроницаемых мембран диализаторов в лечении политравмы

Acute kidney injury in polytrauma is a common and serious complication that significantly worsens the prognosis. Objective: to evaluate the effect of hemodialysis (HD) with high-permeability membranes on the reduction of myoglobin in polytrauma and rhabdomyolysis complicated by acute kidney injury in comparison with plasmapheresis and high-volume hemodiafiltration. Methods: 18 patients with increased creatine phosphokinase (CPK) above 5000 U/E and myoglobin above 1000 ng/ml, stage 3 AKI. The severity of polytrauma was assessed according to the AIS–ISS criteria. The patients were male, from 27 to 47 years old. Results: The average decrease in myoglobin during highflow extended hemodialysis for 2 hours was 31.25% Conclusion: High-flow extended hemodialysis is an alternative method that removes myoglobin and is superior to hemodiafiltration and plasmapheresis in its removal.

CTNI-24. CLINICAL ACTIVITY AND SAFETY OF THE RAF INHIBITOR TOVORAFENIB IN PATIENTS WITH OPTIC PATHWAY GLIOMAS IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY

Abstract BACKGROUND Optic pathway gliomas (OPG) are low-grade gliomas (LGG) comprising 3-5% of pediatric brain tumors. Morbidity may include visual loss (acuity and visual fields), hypothalamic/pituitary dysfunction, and/or impaired motor function. Genomic alterations of MAPK/BRAF are frequent oncogenic drivers in pediatric LGG. Activity of tovorafenib, an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor in OPGs was analyzed. METHODS FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib (420 mg/m2 weekly) in patients 6 months–25 years with BRAF-altered recurrent/progressive LGG or solid tumors. Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints. RESULTS Of the 77 patients enrolled in arm 1 (measurable disease per RANO-HGG), 42 (55%) had tumors located in the optic pathway. Median age at enrollment was 8 years (range: 2–16); 37 (88%) harbored a BRAF fusion and 5 (12%) a BRAF V600E mutation. The median prior lines of systemic therapy was 3 (range: 1–9), with 69% having received prior MAPK inhibitors. Of the 39 evaluable patients (RANO-HGG), the ORR was 59% (1 CR, 22 PRs) with a median time to response (TTR) of 2.8 months; 14 (36%) had stable disease (SD). Per RANO-LGG (n = 42), the ORR was 43% (5 PRs; 13 MRs) with a median TTR of 4.1 months; 20 (48%) had SD. Visual acuity remained stable in 79% (23) of patients (Cycle 9, n = 29 assessed). The most common treatment-related adverse events (TRAEs) of any grade in this subgroup were hair color changes (81%), increased creatine phosphokinase (55%), anemia (48%), maculopapular rash (45%), and fatigue (41%). Dose modifications occurred in 14 (33%) and discontinuations in 3 (7%) patients due to TRAEs. CONCLUSIONS Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.

CTNI-73. ALLIANCE A071601: PHASE II TRIAL OF BRAF/MEK INHIBITION IN NEWLY DIAGNOSED PAPILLARY CRANIOPHARYNGIOMAS

Abstract BACKGROUND Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation. METHODS Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial. RESULTS Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events. CONCLUSIONS Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.

P04.01.B MEK INHIBITORS IN PEDIATRIC RECURRENT SYMPTOMATIC UNRESECTABLE LOW-GRADE GLIOMAS HARBORING MAPK ALTERATION: A SINGLE CENTER EXPERIENCE

Abstract BACKGROUND Treatment of inoperable, recurrent, progressive pediatric low-grade gliomas (pLGGs) remains controversial. Recent studies focused on aberrant activation of the mitogen-activated protein kinase (MAPK) pathway, due to gain of function mutations in RAS or BRAF genes or loss or inactivation of NF1. Selumetinib and trametinib, orally bioavailable and selective MEK1/MEK2 inhibitors (MEKi), act on MAPK pathway. In April 2020 the US Food and Drug Administration and in June 2021 the European Medicines Agency approved selumetinib for inoperable plexiform neurofibromas in Neurofibromatosis type 1 (NF1). We evaluated MEKi efficacy and safety in pLLGs harboring MAPK alteration. MATERIAL AND METHODS From July 2021 to February 2023 eight patients (5 females, 3 males, median age 8 years, range 4-18) were admitted to our hospital for symptomatic, recurrent, inoperable pLGGs (location: 3 hypothalamic-optic chiasm region, 2 posterior fossa, 1 temporo-mesial, 1 quadrigeminal plate, 1 diffuse leptomeningeal; MAPK alteration: 3 NF1 inactivation, 4 KIAA1549/BRAF gene fusion, 1 RNF130/BRAF fusion). MEKi were administered (6 selumetinib, 2 trametinib) after disease progression for failure of previous treatments (6 partial resection, 7 multiple chemotherapies, 2 radiotherapy). MRI assessment was performed every 4 months and radiological response was defined in accordance with RAPNO criteria. RESULTS At first evaluation, 3/8 patients (37,5%) showed a partial radiological response (-64,96% mean volume reduction, range 52,61%-77,19%) and 4/8 (50%) stable disease (0-41.67% volume decrease). Disease progression was observed in a patient heavily pretreated for acute leukemia. One patient with leptomeningeal spreading showed progressive disease at second evaluation. Median time to progression has not yet been reached. Six of 8 patients experienced at least one toxicity. The most frequent toxicities reported were mucocutaneus disorders (rash, mucositis, eczema). Three patients presented creatine phosphokinase (CPK) increase (one grade 2 with rapid normalization after therapy discontinuation). All patients on trametinib had to reduce treatment dose (for skin toxicity or increasing blood pressure). CONCLUSION MEKi, selumetinib and trametinib, represent promising strategies in children with recurrent/progressive LGGs harboring MAPK alterations. In our small series, the treatment was effective and well tolerable in patients with localized disease and without other risk factors. The most common toxicities were CPK elevation and rash. Further studies are needed to identify patients who may benefit most from MEKi treatment and to establish whether such treatments are superior to chemotherapy in front line setting for MAPK altered pLGGs.

P20.05.A USE OF VISMODEGIB IN ADULT PATIENTS WITH NEOPLASTIC MENINGITIS FROM SONIC HEDGEHOG (SHH)-ACTIVATED MEDULLOBLASTOMAS: A CASE REPORT

Abstract BACKGROUND Vismodegib is a SHH-inhibitor that proved to be effective in locally-recurrent SHH-activated medulloblastoma. However, whether vismodegib is effective in case of neoplastic meningitis (NM) as well has not been assessed so far. Here, we present a case of a patient with NM from SHH-activated medulloblastoma who showed a dramatic response to vismodegib. Case Report: A 34-year-old patient was diagnosed with a SHH-activated cerebellar medulloblastoma in 2015. He underwent gross-total resection, cranio-spinal radiotherapy (RT) and 5 cycles of lomustine, vincristine and cisplatin. Then, he remained disease-free until October 2021, when the MRI showed a new single contrast-enhanced nodule in the spine (T10), which was treated with stereotactic RT. However, the following MRI showed a diffuse leptomeningeal involvement, with new multiple linear and nodular lesions. The CSF cytology confirmed the presence of neoplastic cells. Therefore, in April 2022 vismodegib (150 mg daily) was started. The treatment was well tolerated, except for increased creatine phosphokinase (CTCAE v3.0 grade 1). After only 2 months of therapy, a reduction of the meningeal enhancement was seen on MRI, and after 4 months all nodular and linear lesions disappeared. Similarly, CSF cytology became negative after 4 months of treatment. However, after 8 months of treatment (December 2022), the MRI of the spine showed the new appearance of meningeal contrast-enhanced lesions, and CSF cytology confirmed the presence of neoplastic cells. Therefore, vismodegib was dismissed. In few days, the patient (who did not have any symptoms so far) developed severe meningeal symptoms, and palliative care was started, until his death in February 2023. CONCLUSION To our knowledge, this is the first report of an adult patient with NM from SHH-activated medulloblastoma achieving a complete response with vismodegib, even if temporary. Data from larger series are needed to confirm the effectiveness and safety of vismodegib in case of leptomeningeal spread.

Cardiac Biomarker Responses to Acute Exercise in Show Jumping Horses.

Cardiac biomarkers are useful to identify cardiac muscle variations in human and equine medicine. The aim of this study was to investigate the acute effect of a bout of show jumping training on serum activity of cardiac and muscular biomarkers in healthy athletic horses to include cardiac troponin (cTnI), myoglobin (MB), aspartate amino transferase (AST), alanine amino transferase (ALT), creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). Serum samples were collected from seven Italian Saddle horses (three geldings and four mares; 10 ± 3 years; mean body weight 480 ±70 kg), regularly trained for show jumping at rest, immediately after exercise (show jumping simulate trial) and during the recovery period (30 and 60 min after exercise). ANOVA was applied to all parameters, and Pearson correlation coefficient t (r) evaluated. Immediately after exercise there was an increase in cTnI (P < .01), MB (P < .01), and CPK (P < .005); a positive correlation between cTnI and AST and between AST and LDH; and a negative correlation between cTnI and ALT and between ALT and CPK. Thirty minutes after exercise, there was a positive correlation between AST and ALT and between AST and LDH, while 60 mintues after exercise, there was a positive correlation between MB and LDH and a negative correlation between AST and CPK. The results obtained demonstrate the cardiac and muscular response to short-term intense exercise show jumping exercise.

Evaluating Silymarin Extract as a Potent Antioxidant Supplement in Diazinon-Exposed Rainbow Trout: Oxidative Stress and Biochemical Parameter Analysis.

This study aimed to investigate the effects of diazinon on fish, focusing on hepatotoxic biomarkers and the potential protective effects of silymarin supplementation. One hundred eighty rainbow trout were randomly assigned to four groups: control, diazinon exposed (0.1 mg L-1), silymarin supplemented (400 mg kg-1), and diazinon + silymarin. Blood samples and liver tissue were collected after 7, 14, and 21 days of exposure to analyze biochemical parameters and oxidative biomarkers. Diazinon exposure in fish resulted in liver damage, as indicated by increased antioxidant enzyme activities in the hepatocytes. Silymarin showed the potential to mitigate this damage by reducing oxidative stress and restoring enzyme activities. Nevertheless, diazinon increased creatine phosphokinase activity, which may not be normalized by silymarin. Exposure to diazinon increased glucose, triglyceride, and cholesterol levels, whereas total protein, albumin, and globulin levels were significantly decreased in fish. However, silymarin controlled and maintained these levels within the normal range. Diazinon increased creatinine, urea, uric acid, and ammonia contents. Silymarin could regulate creatinine, urea, and uric acid levels while having limited effectiveness on ammonia excretion. Furthermore, diazinon increased malondialdehyde in hepatocytes, whereas administration of silymarin could restore normal malondialdehyde levels. Overall, silymarin showed potential as a therapeutic treatment for mitigating oxidative damage induced by diazinon in fish, but its effectiveness on creatine phosphokinase, glutathione reductase, and ammonia may be limited.

Aggravation of TGFβ1-Smad Pathway and Autoimmune Myocarditis by Fungicide (Tebuconazole) Exposure.

Myocarditis is an inflammatory cardiac disorder and the primary cause of heart failure in young adults. Its origins can be attributed to various factors, including bacterial or viral infections, exposure to toxins or drugs, endocrine disruptors (EDs), and autoimmune processes. Tebuconazole (TEB), which is a member of the triazole fungicide family, is utilized to safeguard agricultural crop plants against fungal pathogens. Although TEB poses serious threats to mammal health, the information about how it induces toxic effects through various pathways, particularly in autoimmune diseases, are still limited. Thus, the aim of this paper was to evaluate the effect of TEB exposure in autoimmune myocarditis (AM). To induce AM, rats were immunized with porcine cardiac myosin and exposed to TEB for 21 days. Thereafter, animals were sacrificed, and histological, biochemical, and molecular analyses were performed. TEB exposure increased heart weight, systolic blood pressure and heart rate already augmented by AM. Additionally, it significantly increased creatine phosphokinase heart (CK-MB), creatine phosphokinase (CPK), cardiac troponin T (cTnT), and cardiac troponin I (cTnI), as compared to the control. From the histological perspective, TEB exacerbates the histological damage induced by AM (necrosis, inflammation and cell infiltration) and increased fibrosis and collagen deposition. TEB exposure strongly increased pro-inflammatory cytokines and prooxidant levels (O2-, H2O2, NO2-, lipid peroxidation) and reduced antioxidant enzyme levels, which were already dysregulated by AM. Additionally, TEB increased NOX-4 expression and the TGFβ1-Smads pathway already activated by AM. Overall, our results showed that TEB exposure strongly aggravated the cardiotoxicity induced by AM.

Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours

BackgroundBromodomain and extraterminal domain (BET) inhibitors have demonstrated efficacy in solid tumours and haematological malignancies. BI 894999 is a novel oral BET inhibitor that has demonstrated potent antitumour activity in preclinical studies. Patients and methods1367.1 was an open-label, Phase Ia/Ib dose-finding study evaluating BI 894999 once daily in patients with advanced solid tumours (Schedule A: 0.2, 0.5, 1.0, 1.5, 2.0, and 5.0 mg, Days 1–21/21-d cycle; Schedule B: 1.5, 2.0, and 2.5 mg, Days 1–15/21-d cycle; Schedule C: loading dose 5.0, 6.0, or 7.0 mg on Day 1 followed by maintenance dose 2.5, 3.0, or 3.5 mg, Days 2–7 and 15–21/28-d cycle); 77 patients were enrolled. NCT02516553. ResultsGrade ≥3 dose-limiting toxicities (DLTs) were reported in 8/21, 5/25, and 9/31 patients for Schedules A, B, and C, respectively. Thrombocytopenia was reported as a DLT in 28.6%, 4.8%, and 9.7% for Schedules A, B, and C, respectively. Other DLTs occurring in ≥1 patient were troponin T increase (13.6%), hypophosphataemia (4.5%), and elevated creatine phosphokinase (3.0%). Disease control was achieved in 23.8%, 24.0%, and 29.0% of patients for Schedules A, B, and C, respectively. A partial response was achieved in 9.5% and 4% of patients with Schedules A and B, respectively. The best response with Schedule C was stable disease. ConclusionThe 1.5, 2.5, and 6.0/3.0 mg doses in Schedules A, B, and C, respectively, were declared as maximum tolerated dose. Based on the strength of these data, BI 894999 was further evaluated in a Phase Ib trial.

LGG-09. CLINICAL ACTIVITY OF PAN-RAF INHIBITOR TOVORAFENIB IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY

Abstract Genomic alterations of BRAF are common oncogenic drivers in pediatric low-grade glioma (pLGG). Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II panRAF inhibitor. FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 includes patients 6 months-25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m2 (≤600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by RANO criteria and determined by blinded independent review. As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2-21). Patients had received a median of 3 prior lines of systemic therapy (range: 1-9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a tumor BRAF fusion/rearrangement (83%) and 13 (17%) a V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7-16.8); 59 patients (77%) remained on treatment at data cutoff. ORR in 69 RANO-evaluable patients was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Two patients (3%) discontinued tovorafenib due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented. Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with refractory BRAF-altered LGG.

CLINICAL CASE OF DUCHENNE MYODYSTROPHY

The paper describes a clinical case of Duchenne myodystrophy at the stage of manifestation of clinical manifestations. The problems of diagnosing mutations in the DMD gene are considered. The paper presents clinical and laboratory data for Duchenne myodystrophy. It is noted that the difficulty of clinical diagnosis of Duchenne myodystrophy is associated with the presence of a preclinical period, in which the main diagnostic marker is an increase in transaminases, lactate dehydrogenase and creatine phosphokinase, as well as varying degrees of severity of clinical manifestations. Low alertness of doctors to hereditary pathology at the preclinical stage of the disease was noted. Molecular genetic diagnosis is difficult due to the large size of the DMD gene, which, when the reading frame is violated, gives a large number of different mutation variants. It is noted that modern pathogenetic therapy of this disease is ineffective, and the most promising areas of etiological treatment are gene therapy and cell technologies. Conclusion. Difficulties in diagnosing hereditary myodystrophy are associated with low awareness and alertness of doctors regarding hereditary pathology. For the effective treatment of patients with Duchenne myodystrophy, it is necessary to introduce etiological methods of treatment into medical activities

Clinical activity of pan-RAF inhibitor tovorafenib in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY-1 (PNOC026) study.

10004 Background: Pediatric low-grade gliomas (LGGs) are the most common brain tumors of childhood. Genomic alterations of BRAF ( KIAA1549-BRAF fusions, 50–60% and BRAF V600E mutations, 5–15%) are the most frequent oncogenic drivers in pLGGs. Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II pan-RAF inhibitor. Tovorafenib has demonstrated clinically meaningful responses in 24/35 patients (2 CR, 7 PR and 15 SD) in the pediatric phase 1B PNOC014 (NCT03429803) trial in patients with RAF-altered cancers (Wright, SNO 2022). Methods: FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 of FIREFLY-1 includes patients 6 months–25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m2 (not to exceed 600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by Response Assessment in Neuro-Oncology (RANO) criteria and determined by blinded independent review. Results: As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2–21). Patients were pretreated with a median of 3 prior lines of systemic therapy (range: 1–9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a BRAF fusion/rearrangement (83%) in their tumors, and 13 (17%) had a BRAF V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7–16.8), with 59 patients (77%) remaining on treatment at the time of data cutoff. Per independent assessment in 69 RANO-evaluable patients, ORR was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations, including those previously treated with MAPK inhibitors. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Tovorafenib dose modifications occurred in 16 (21%) and discontinuations in 2 (3%) patients due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented at the meeting. Conclusions: Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with recurrent/progressive BRAF-altered pLGG. LOGGIC/FIREFLY-2 (NCT05566795), a global, phase 3 trial is evaluating once-weekly tovorafenib monotherapy in newly-diagnosed patients with pLGG harboring a known activating RAF alteration. Clinical trial information: NCT04775485 .

P409 MYOCARDITIS OR RHABDOMYOLYSIS WITH MYOCYTE NECROSIS?

Abstract Rhabdomyolysis is a clinical syndrome involving skeletal muscle tissue characterized by muscle weakness, myalgias and increased creatine phosphokinase (CPK) levels, usually 5 times up the normal limit. During rhabdomyolysis troponin (TNI) may be released due to mismatch between oxygen supply and demand, cytokine and endotoxin toxicity, presence of heterophile antibodies that cause false positive results and cross–reactivity between TNI isoforms produced by skeletal muscle and TNI isoforms produced by cardiac muscle. The triggering causes are multiple and include viral infections and genetic pathologies involving skeletal muscles. Genetic mutations of filamin C can cause myofibrillar myopathies, a heterogeneous group of neuromuscular disorders characterized by myopathy involving proximal and distal muscles that often occur in adulthood and may be associated with cardiomyopathies. Genetic mutations of filamin C can also be found in healthy adults because some variants have a subclinical expression. Case Report A 34 years old man came to the Emergency Department (ED) with fever, diarrhoea, asthenia and anuria. His past medical history was characterized by 4 episodes of myocarditis (TNI value increased up to 21 ng/dl, reduced left ventricular ejection fraction to 40%) all occurring in conjunction with acute gastroenteritis. The genetic analysis, performed six months before, showed a heterozygous mutation of the gene coding for filamin C. Blood tests performed in ED showed an increase in CRP values (4.8mg/dl), in transaminases values and a modest increase in troponin values (0.96ng/dl) without electrocardiographic and echocardiographic abnormalities (ejection fraction was preserved). He was admitted to Emergency Cardiology Department with a diagnosis of myocarditis. The CPK value resulted to be 22.503 U/l (n.v. 60 –190 U/l). Cardiac MRI underlined no signs of acute myocarditis. The patient, treated with intravenous fluid therapy, after one week showed clinical improvement and normalization of CPK and TNI values. Conclusions in the present case the acute gastrointestinal event was the trigger of rhabdomyolysis and not of an acute myocarditis as initially erroneously interpreted, in a patient carrying a genetic mutation predisposing to myopathies. Follow–up will evaluate whether and to what extent the genetic abnormality will lead to the development of myopathy and/or cardiomyopathy.

Prevalence and Risk Factors Associated With Natural Infection by Trypanosoma evansi in Campeiro Horses

Campeiro horse is a breed locally adapted to the Santa Catarina plateau region and its main characteristic is the gait, it is known as “Marchador das Araucárias.” It is a breed considered in danger of extinction, being fundamental the search for the preservation of this important genetic resource. Surra, caused by the protozoan Trypanosoma evansi, is among the diseases that affect horses. However, there are no data on the prevalence of infection in Campeiro horses. This study aimed to determine the prevalence of T. evansi in Campeiro horses, correlate hematology and serum biochemistry, and identify possible risk factors. Blood samples were collected by venipuncture of 214 Campeiro horses, 50 males and 164 females, aged between 3 months and 27 years, from 16 properties located in the States of Santa Catarina, Rio Grande do Sul, and Paraná. An epidemiological questionnaire was carried out with the owners to analyze the associated risk factors. The blood samples were submitted to polymerase chain reaction, immunofluorescence antibody test, complete blood count, and serum biochemistry. The prevalence was 14% of positive animals by polymerase chain reaction and 59% by immunofluorescence antibody test . There was an increase in hematocrit, and in the number of basophils, a decrease in plasmatic fibrinogen, and in the enzymatic activity of alanine aminotransferase, aspartate aminotransferase, and urea, and an increase in creatine phosphokinase and creatinine in positive animals, which is possibly unrelated to the infection. The data obtained through the epidemiological questionnaires showed no difference. Therefore, T. evansi is present in the South of Brazil, with a high prevalence in Campeiro horses.

Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX)

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Glycine protects against doxorubicin-induced heart toxicity in mice

Doxorubicin (DOXO) is a well-known cancer chemotherapeutic. However, its toxic effect on the heart limits its clinical application. This study aimed to assess the effectiveness of glycine administration to counteract the DOXO-induction of cardiomyopathy in mice. Fifty male albino mice were divided into five groups (n = 10/group) as follows: control, DOXO, Gp100, Gp150, and Gp200. Histopathological examination of the heart, and biochemical examinations for heart function (creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST)), inflammation (tumor necrosis factor-alpha (TNF-α) and interleukin 10 (IL-10)), oxidative stress (malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase, nitric oxide (NO), and uric acid), kidney function (urea and creatinine), and minerals (calcium, phosphorus, sodium, and potassium) were carried out. Cardiomyopathy induced by DOXO treatment (15 mg/kg total dose) was ascertained via pathological alterations seen in heart tissue and verified biochemically via increases (P < 0.001) in CPK, LDH, AST, TNF-α, IL-10, MDA, NO, Na, and K levels along with decreases (P < 0.001) in GSH, SOD, catalase, and uric acid. Glycine co-treatment, using doses of 100, 150, and 200 mg/kg, in a dose-dependent manner, displayed ameliorated heart architecture, significantly (P < 0.001) improved biochemical heart function tests, reduced oxidative stress and inflammation, and controlled mineral levels. The positive actions of glycine in DOXO-induced cardiotoxicity amelioration via modulating oxidative stress, inflammation, and immunity are confirmed. Glycine antioxidative properties may be behind its positive outcomes. Finally, we present glycine as a worthy possible option against DOXO-induced heart damage after more validation.