Melanoma was recognized as the most dangerous type of skin cancer, especially for metastatic melanoma. Before 2011, metastatic melanoma was considered a devastating disease, the standard-of-care treatments during this time included dacarbazine chemotherapy and immunotherapy with the cytokine IL-2, and the median overall survival was only 9 months. Fortunately, the treatment landscape has shifted dramatically during recent years [1]; targeted therapies and immunotherapies have been shown to improve clinical outcomes for patients with unresectable or metastatic disease [1,2,3,4,5]. I-Doser DRG With All Doses
*Download Zip* https://tinurli.com/2wHoaJ This phase I trial was first-in-human trial to evaluate the tolerability, preliminary efficacy, pharmacokinetics of HL-085 in patients with advanced *NRAS*-mutated melanoma and explored potential biomarkers of treatment efficacy. We report here the results of a phase 1 trial of HL-085. This study was approved by local institutional review boards and ethics committee at each trial center and was conducted in line with good clinical practice guidelines, Declaration of Helsinki, and relevant regulations. Prior to study initiation, all patients provided written informed consent. The study protocol was registered at clinicaltrials.gov (NCT03973151). Efficacy evaluations were performed by computed tomography or magnetic resonance imaging on baseline (within 28 days before the first dose), cycle 2 day 1, and then every 2 cycles (8 weeks) from cycle 3 day 1(whether CT or MRI is selected, the evaluation methods and parameters need to be consistent in each cycle). Response was evaluated by the investigator according to RECIST, version 1.1. The efficacy analysis was conducted in patients who have had at least one tumor evaluation, and when someone meets the partial response (PR) or complete response (CR) criteria, efficacy will be confirmed again at a subsequent time point (interval of at least 4 weeks) before CR or PR is granted. Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (median age: 56 years; 47.6% women), including 30 patients in the dose-escalation phase and 12 patients in the dose-expansion phase. Twenty-23 patients (23/42, 54.8%) were acral melanoma, and 13 patients (13/42, 31.0%) were mucosal melanoma. Prior treatment included surgery in 41 patients (41/42, 97.6%), radiotherapy in 5 patients (5/42, 11.9%) and medication in 36 patients (36/42, 85.7%). A total of 17 (17/42, 40.5%) patients had prior treatment with PD-1 and PD-L1 inhibitors. Baseline characteristics are summarized in Table 1. Drug-related AEs leading to drug interruption or dose reduction were observed in 19 patients (19/42, 45.2%); all dose occurred, except 0.5 mg, 1 mg, and 2 mg dose group. The most common AE include the following: increased CK (6/42, 14.3%), fatigue (3/42, 7.1%), peripheral edema, acne-like dermatitis, ambiguous state of consciousness 4.8% (2/42). In this trial, ambiguous state of consciousness were observed in 2 patients, 12 mg and 18 mg dose group respectively. The one occurred in 12 mg dose, died 8 days later due to extensive disease progression and abdominal tumor rupture and hemorrhage; the investigators evaluated that the ambiguous state of consciousness was associated with disease progression. The other one occurred in 18 mg dose, symptoms disappeared and no sequelae after 5 days later. All the others occurred in 1 case. Skin toxicity were the most frequent treatment-related AEs in this study (Table 2) especially for rash, but all of them were grade 1 or 2. The second most common AE was increased CK, most of which were asymptomatic and only a small proportion of patients had mild muscle soreness and fatigue. Six patients (6/42, 14.3%) with increased CK were resolved upon interruption or dose reduction of HL-085. Increased AST, increased ALT, diarrhea, face edema, and peripheral edema were manageable with concomitant medications. Among 27 patients with baseline blood samples available for ctDNA analysis, *NRAS* mutation was detected in 21 samples (21/27, 78%). Positive *NRAS* mutation status in blood samples was consistent with corresponding tissue samples in 100% of cases (Additional file 1: Fig. S2). Our findings showed that HL-085 was well tolerated, with the most common AEs of skin-related AEs and increased CK were manageable. No DLT occurred in the dose- escalation phase and MTD was therefore not reached. Anti-tumor activity were first observed in the 4 mg dose cohort with PR first observed at the 9 mg dose, suggesting dose-dependent anti-tumor activity of HL-085. Toxicity of HL-085 increased with dose (respiratory, thoracic and mediastinal disorders, cardiac disorders and eye disorders requiring discontinuation of HL-085 in the 15 and 18 mg dose cohorts). Based on the absence of severe toxicity and promising evidence of efficacy in the dose-escalation phase, 12 mg BID was identified as the RP2D for HL-085 and was selected for dose expansion. In conclusion, this phase I trial established the RP2D of HL-085 as 12 mg BID in patients with advanced melanoma with *NRAS* mutations. HL-085 had an acceptable tolerability profile and showed promising clinical benefits in this setting, supporting further investigation of HL-085 12 mg BID in clinical trials. Phase 2 monotherapy studies in *NRAS* mutant melanoma and novel combination studies are ongoing. We are the leading provider of artisan brainwave doses and software. Our products are used by millions of people worldwide to help achieve a simulated mood or experience through the use of special binaural audio. Many use binaural brainwave audio to relax, have a recreational experience, enhance meditation, chakra and yoga, holistic balance - and so much more. With hundreds of available doses, the possibilities are endless. 1. Click to *DOWNLOAD* the iDoserFree.dmg Disk Image. DOWNLOAD 2. Delete any previous versions of the iDoser App from your Applications Folder and then Double-Click the iDoserFree.dmg Disk Image. Drag the iDoser Free App to your Applications Folder. 3. Run the iDoser Free App from your Applications Folder or drag to your Dock for easy access. Make sure you have administrator rights on the computer you are installing to. If upgrading, please note that doses are now installed to /Music/Dose Files/ folder. In previous versions this was the /Documents/Dose files/ folder. Be sure to move your old doses to the new folder. For additional troubleshooting please read IDoser_ReadMe.html file located in the iDoserFree.dmg Disk Image or CLICK HERE to contact an advisor. Template:AdvertI-Doser is an application which claims to use binaural beats in order to simulate the effect of various drugs and other altered states of consciousness. Users can purchase "doses" of their choice from the online store. The I-Doser application then plays "dose" files which attempts to create the effects of the chosen drug. Its effects are varied, and the length of the effects depend on your state of mind when the dose is administered and the type of dose. Brentuximab vedotin has already been combined with standard therapy in a sequential strategy and concurrently with chemotherapy regimens such as ESHAP (etoposide, methylprednisolone, cytarabine and cisplatin) before HDC-ASCT,116 and resulted in a CMR rate of more than 75% prior to HDC-ASCT. However, the combination of BV with multi-agent chemotherapy can be associated with significant toxicity.108 Tumor burden reduction by a combination of BV and DHAP treatment is attractive because DHAP by itself is well tolerated in patients with R/R cHL and results in 20% complete remission (CR) and 70% partial remission [PR; based on conventional computed tomography (CT) scanning] and 50-60% metabolic CR (CMR) while stem cell mobilization potential is maintained.12 In this multicenter, open-label, phase I dose-escalation study, patients aged 18 years or older with a histologically confirmed CD30 R/R cHL were treated with three cycles of BV-DHAP, followed by HDC (BEAM regimen: carmustine, etoposide, cytarabine and melphalan) with an ASCT rescue. Brentuximab vedotin was administered at the full dose of 1.8 mg/kg on the first day of each cycle of DHAP, with escalation of the dose of cisplatin and cytarabine. BV was combined with either 75% of the dose cisplatin on day 1 and 75% of cytarabine on day 2 [dose level (DL) 1], 75% cisplatin and 100% cytarabin (DL2) or full dose of all agents (DL3). Full-dose cisplatin was defined as 100 mg/m and full-dose cytarabin was defined as 2 g/m q 12 hours (2 doses). Dexamethasone 40 mg was given at day 1-4. Granulocyte-colony stimulating factor (G-CSF) (Neulasta) 6 mg fixed dose was given subcutaneously on day 5 of DHAP cycles 1 and 3 from DL2 onwards after prolonged neutropenia requiring delay of the next cycle was seen in 2 out of 3 patients treated at DL1. For stem cell mobilization, G-CSF 5 μg/kg was administered twice daily from day 10 of BV-DHAP cycle 2 until stem cell harvest. A total of ten serious adverse events (SAEs) occurred in 4 patients, all at DL3. One patient experienced hypokalemia grade 4 as well as acute liver failure grade 4 lasting longer than fourteen days [occurring at 11 days after BV (BV-DHAP cycle 3) and 2 days after initiation of amoxicillin/clavulanic acid]. A liver biopsy showed nonspecific toxicity. This patient also experienced atrial fibrillation grade 3 and was treated with cardioversion. These last two SAEs were possibly related to BV and classified as dose-limiting toxicities (n=1, DL3). The same patient experienced fever of unknown origin grade 3, not related to BV (no neutropenia at the time of fever). A second patient exhibited elevated transaminases grade 3 unlikely to be related to BV. A third patient experienced a central venous catheter-related infection grade 3 (not related to BV), varicella zoster reactivation grade 3 after BV-DHAP cycle 3 (no prophylaxis was indicated), and fever of unknown origin grade 3. The fourth patient experienced acute kidney injury grade 3 (resolved) and pneumonitis grade 3 (resolved). These SAEs were considered unlikely to be related to BV treatment. eebf2c3492 -- You received this message because you are subscribed to the Google Groups "beets" group. To unsubscribe from this group and stop receiving emails from it, send an email to [email protected]. To view this discussion on the web visit https://groups.google.com/d/msgid/beets-users/04297419-1fa8-4f4b-9817-23c9f36c82d8n%40googlegroups.com.
