Randomized Phase 2b Research Articles

Durable improvements in atopic dermatitis in the head and neck and across other anatomic regions with rocatinlimab

In a randomized phase 2b trial (NCT03703102) for adult patients with moderate-to-severe atopic dermatitis (AD), treatment with the T cell rebalancing anti-OX40 receptor antibody rocatinlimab (AMG 451/KHK4083) led to significant improvements in clinical measurements versus placebo including whole-body Eczema Area and Severity Index (EASI) score. AD manifestations can impact variable anatomic regions, and involvement of the head and neck, a sensitive, hard-to-treat area, can negatively impact quality of life. In this post hoc analysis, we investigated response to rocatinlimab treatment across anatomic regions, including the head and neck. Least squares mean change from baseline to Week 56 in EASI score was analyzed by anatomic region (head and neck, trunk, upper extremities, or lower extremities) for patients with baseline moderate-to-severe AD in the respective anatomic region, using mixed models for repeated measures. Rocatinlimab groups were compared with placebo at Week 16. The proportion of patients achieving at least 75% reduction from baseline in EASI (EASI-75) was calculated. Probability of relapsing in EASI-75 during the off-treatment follow-up period (Weeks 36–56) was estimated using a Kaplan − Meier approach. At Week 16, decrease from baseline in mean EASI score was greater with all rocatinlimab regimens versus placebo across all anatomic regions for patients with baseline moderate-to-severe AD in the respective region (all P < 0.001). EASI scores continued to improve on treatment after Week 16 and were maintained during the off-treatment period across all regions. Among patients with baseline moderate-to-severe AD in the head and neck (n = 219; rocatinlimab, n = 174; placebo, n = 45), mean difference (rocatinlimab vs placebo) at Week 16 in LS mean percent change in head and neck EASI score ranged from − 30.4% to − 42.6% across treatment regimens. In patients who received rocatinlimab from the start of the trial, 47% − 71% achieved EASI-75 in the head and neck at Week 36. Among EASI-75 responders at Week 36, the probability of relapsing in EASI-75 in any region was low (< 25% in the head and neck) 20 weeks after treatment discontinuation until Week 56.Rocatinlimab treatment led to durable improvements in AD across multiple anatomic regions, including the sensitive head and neck region.Graphical abstract

A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease

Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD ,estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks treatment with standard of care plus subcutaneous cotadutide up-titrated to100, 300, or 600 μg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once-weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m2, geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium–glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 μg (−43.9% [95%confidence interval −54.7 to −30.6]) and 600 μg (−49.9% [−59.3 to −38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 μg were comparable to semaglutide. Thus, our study shows that in patients with T2Dand CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study.

INTerpath-001: Pembrolizumab with V940 (mRNA-4157) versus pembrolizumab with placebo for adjuvant treatment of high-risk stage II-IV melanoma.

TPS9616 Background: The anti−PD-1 antibody pembrolizumab is approved as adjuvant therapy for stage IIB-C and stage III melanoma by AJCC 8th ed, following complete resection. Adjuvant pembrolizumab has improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk melanoma, but many patients experience disease recurrence. In the randomized phase 2b KEYNOTE-942 study, the individualized neoantigen therapy V940 showed improved RFS and DMFS when used in combination with pembrolizumab versus pembrolizumab monotherapy in patients with stage III or IV melanoma. INTerpath-001 (NCT05933577) is a double-blind phase 3 randomized controlled trial designed to evaluate the efficacy and safety of adjuvant pembrolizumab plus V940 versus pembrolizumab plus placebo in patients with resected high-risk stage II-IV melanoma. Methods: Eligible patients are aged ≥18 years with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th ed and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients are ineligible if they have received any prior systemic therapy and if more than 13 weeks has elapsed between last surgical resection and first dose of pembrolizumab. Patients with ocular or mucosal melanoma and past or current in-transit metastases or satellitosis are excluded. All patients must provide a blood sample and a formalin-fixed, paraffin-embedded tumor sample for sequencing. Patients will be stratified by risk (IIB, IIC, IIIA, and IIIB vs IIIC/D and IV) and age (&lt;65 years vs ≥65 years). Approximately 1089 patients will be randomly assigned 2:1 to receive pembrolizumab 400 mg plus V940 1 mg or pembrolizumab 400 mg with placebo. Pembrolizumab will be administered intravenously every 6 weeks and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal. The primary end point is RFS by investigator review. Secondary end points are DMFS by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% CIs will be estimated using a stratified Cox regression model with the Efron method of handling ties. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05933577 .

IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial

Inflammation mediated by interleukin-6 (IL-6) is strongly associated with cardiovascular risk. Here we evaluated clazakizumab, a monoclonal antibody targeting the IL-6 ligand, in a phase 2b dose-finding study. Adults with cardiovascular disease and/or diabetes receiving maintenance dialysis with high-sensitivity C-reactive protein (hs-CRP) ≥ 2 mg l−1 at baseline were randomized to receive clazakizumab (2.5 mg, 5 mg or 10 mg, n = 32 per dose group) or placebo (n = 31) every 4 weeks. The primary endpoint was the change from baseline in hs-CRP to week 12, expressed as the geometric mean ratio. Clazakizumab treatment signficantly reduced serum hs-CRP concentrations at week 12 by 86%, 90% and 92% relative to placebo in patients randomized to 2.5 mg, 5 mg or 10 mg clazakizumab, respectively (all P < 0.0001), meeting the primary outcome. With regard to secondary endpoints, clazakizumab treatment reduced serum fibrinogen, amyloid A, secretory phospholipase A2, and lipoprotein(a) concentrations, as well as increased mean serum albumin concentrations at 12 weeks, relative to placebo. The proportion of patients who achieved hs-CRP < 2.0 mg l−1 was 79%, 82% and 79% in the 2.5 mg, 5 mg and 10 mg clazakizumab groups, respectively, compared with 0% of placebo-treated patients. With regard to safety, no cases of sustained grade 3 or 4 thrombocytopenia or neutropenia were observed. Serious infections were seen with similar frequency in the placebo, clazakizumab 2.5 mg and clazakizumab 5 mg groups, but were numerically more frequent in the clazakizumab 10 mg group. The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events. ClinicalTrials.gov registration: NCT05485961.

Firstline Treatment with Ruxolitinib Versus Best Available Therapy in Patients with Polycythemia Vera: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Introduction: Polycythemia vera (PV) is characterized by trilineage blood cell expansion, PV-associated symptoms, and the risk of thromboembolic complications, progression to post-PV myelofibrosis, and acute leukemia. Cytoreductive treatment with hydroxyurea (HU) or ropeginterferon-alpha is approved in EU for the treatment of high-risk patients (pts) with PV. In addition, ruxolitinib (RUX) is approved for HU-intolerant/-resistant PV. However, RUX vs. best available therapy (BAT) has not been investigated as first-line treatment of pts with untreated PV. We hypothesized that RUX may have higher efficacy in such early-line PV pts. Methods: The clinical trial entitled “Ruxolitinib versus Best Available Therapy in pts with high-risk PV or high-risk ET” (RuxoBEAT; NCT02577926) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 190 pts in each stratum. Crossover from BAT to RUX is possible in eligible pts after 6 months. Pts with PV in the RUX arm received a starting dose of 10 mg BID and may increase their dose up to 20 mg BID. The primary endpoint is the clinicohematologic complete response (CR) rate at month 6, as defined by Barosi et al (Blood 2009), using a strict score of zero for the four symptoms by patient-reported outcome measures (PROM, Table 2) and an adjusted level alpha = 0.005 at a power of 80%. Secondary endpoints include overall response rate (CR+PR), freedom from phlebotomy, changes in blood counts, spleen size, and PROM, using p values descriptively. The interim trial data were recently reviewed by the DMC, and, due to the low likelihood of reaching the primary endpoint (CR rate improvement), the DMC has recommended that the trial should continue without recruitment of new pts. Therefore, this pre-specified interim analysis was performed after 78 (instead of 95) PV pts were randomized 1:1 to RUX vs. BAT. A maximum of 6 weeks of previous PV-directed therapy was allowed. Differences between RUX and BAT at month 6 and between baseline and end of month 6 data for each treatment were calculated using Fisher´s exact test/ McNemar Test (for unpaired/ paired binary variables) or the Mann-Whitney-U test/ Wilcoxon signed-rank test (for unpaired/ paired ordered or continuous variables). Results: 78 first-line pts (33% were pre-treated for a median of 22 days [range 1-42]) were included in the intention-to-treat set (n=44 vs 34 randomized to RUX vs. BAT, resp.) and analyzed at the 6-month time point. Baseline characteristics are listed in Table 1. In pts on RUX or BAT, CR rates at 6 months were comparable (2.3% and 2.9%, p=1.0), while overall response (CR+PR) rates were 77.3% with RUX and 55.9% with BAT (p=0.054). Also, at month 6 (Table 2), pts on RUX showed significantly lower hematocrit (40.8% vs 42.1%, p=0.046), and PROM symptom points for pruritus (1 vs 4, p=0.001) and fatigue (2.5 vs 5, p=0.031), and a trend towards less headache, abdominal discomfort, and weight loss, while the number of platelets was lower with BAT vs. RUX (254/nl vs 386/nl, p=0.013). There was no difference between RUX and BAT in the number of white blood cells (WBC), spleen size, or other symptoms at this time point. When each treatment arm was analyzed separately for changes between baseline and month 6, RUX treatment significantly reduced platelet counts, WBC, hemoglobin and hematocrit, phlebotomy rates, spleen size and fraction of pts with splenomegaly (Table 2), and significantly improved PROMs for pruritus, early satiety, and quality of life. During the same time period, BAT significantly reduced platelet counts, WBC, hematocrit, and phlebotomy rates, but failed to impact on hemoglobin, spleen size, fraction of pts with splenomegaly, or any of the symptoms (Table 2). Safety analysis revealed 301 adverse events (AE) in both assigned treatment groups, including 153 AE in the RUX and 148 AE in the BAT group (11.8% and 8.1% grade ≥3, resp.). There was no significant difference in the percentage of grade ≥3 AE between both groups (p=0.358), and there were no consistent patterns of grade ≥3 AE in either of the two arms. Conclusion: In this interim analysis, first-line treatment with ruxolitinib for 6 months in high-risk pts with PV led to clinically meaningful improvements in overall response, hemoglobin and hematocrit, phlebotomy rates, splenomegaly, and patient-reported pruritus and fatigue severity, while BAT only improved platelet counts, WBC, hematocrit, and phlebotomy rates, without having an impact on symptoms.

Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Comprehensive Analysis of Randomized Phase 2B Trial of Proton Beam Therapy Versus Intensity Modulated Radiation Therapy

Lymphocytes play an important role in antitumor immunity; however, they are also especially vulnerable to depletion during chemoradiation therapy (CRT). The purpose of this study was to compare the incidence of grade 4 lymphopenia (G4L) between proton beam therapy (PBT) and intensity modulated photon radiation therapy (IMRT) in patients with esophageal cancer treated with CRT in a completed randomized trial and to ascertain patient heterogeneity to G4L risk based on treatment and established prognostic factors. Between April 2012 and March 2019, a single-institution, open-label, nonblinded, phase 2 randomized trial (NCT01512589) was conducted at the University of Texas MD Anderson Cancer Center. Patients were randomly assigned to IMRT or PBT, either definitively or preoperatively. This secondary analysis of the randomized trial was G4L during concurrent CRT according to Common Terminology Criteria for Adverse Events version 5.0. Among 105 patients evaluable for analysis, 44 patients (42%) experienced G4L at a median of 28 days after the start date of concurrent CRT. Induction chemotherapy (P=.003), baseline absolute lymphocyte count (P < .001), radiation therapy modality (P=.002), and planning treatment volume (P=.033) were found to be significantly associated with G4L. Multivariate classification analysis partitioned patients into 5 subgroups for whom the incidence of G4L was observed in 0%, 14%, 35%, 70%, and 100% of patients. The benefit of PBT over IMRT was most pronounced in patients with an intermediate baseline absolute lymphocyte count and large planning treatment volume (P=.011). This is the first prospective evidence that limiting dose scatter by PBT significantly reduced the incidence of G4L, especially in the intermediate-risk patients. The implication of this immune-sparing effect of PBT, especially in the context of standard adjuvant immunotherapy, needs further examination in the current phase 3 randomized trials.

First-in-class oral innate immune activator BXCL701 combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) variant: Randomized phase 2b trial.

TPS5109 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP8/9 &amp; DPP4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 &amp; IL-1ß, bridging innate &amp; adaptive immunity. BXCL701 + pembrolizumab evaluated in a Phase 2 study, in mCRPC patients with SCNC. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Final results of Phase 2a presented at ASCO GU 2023 (abstract #176) after enrollment of 28 evaluable SCNC patients. 7 (25%) patients achieved a composite response, primary endpoint of trial. In patients with measurable disease (n = 25), RECIST 1.1-defined partial response (PR) observed in 5 (20%) patients (4 confirmed PR + 1 uPR). Disease control rate (complete response + PR + stable disease) was 48% (12 patients). Median duration of response for both composite responses and RECIST-defined PRs was 6+ months as of data cutoff on 19-DEC-22. 6 / 34 patients (18%) in safety population experienced serious adverse events (SAEs) possibly related to BXCL701 or pembrolizumab, and 6 (18%) patients discontinued any drug due to an AE. No evidence found that BXCL701 potentiates immune-related AEs related to immune checkpoint inhibitors. DPP9 overexpression was identified as a potential predictive biomarker for BXCL701 response; biomarker evaluation is ongoing and additional findings will be presented at an upcoming medical meeting. Since SCNC cohort showed encouraging efficacy in Phase 2a, the Phase 2b portion of study was initiated to evaluate SCNC variant in a potential registrational randomized study. Methods: Patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, are randomized 2:1 to receive BXCL701 + pembrolizumab (n = 40) or BXCL701 monotherapy (n = 20). Patients are required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy also permitted entry with prior approval by sponsor). Patients receive pembrolizumab (200 mg IV q3week Day 1) + BXCL701 or BXCL 701 alone (0.2 mg BID Days 1-7 with step-up to 0.3 mg BID Days 8-14, and 0.3 mg BID Days 1-14 of subsequent 21-day cycles). Primary endpoint is response rate defined by RECIST 1.1 criteria. Secondary objectives are ≥-50% decline in PSA from baseline, OS, duration of response, rPFS, and PSA PFS. Exploratory biomarkers and changes in relevant immune effector cells are also evaluated. Phase 2a activity threshold for accrual was met. ClinicalTrials.gov Identifier: NCT03910660. Clinical trial information: NCT03910660 .

Efficacy and safety of Kras inhibitors in pancreatic cancer: A systematic review of clinical trials.

e16297 Background: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive tumor and is one of the leading causes of cancer related deaths worldwide. Kirsten Rat Sarcoma (KRAS)mutation resulting in tumor cell proliferation and cancer progression is a frequently mutated oncogene in various cancers and is approximately seen in 90% of pancreatic ductal adenocarcinoma. Efforts are being done to target Kras mutation in the last 3–4 decades. Here in, we report the results of the systemic review of clinical trials done on chemotherapeutic agents targeting Kras mutated pancreatic cancer. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltrials.gov, and Embase with mesh terms, “pancreatic neoplasm’’ and “kras” from the inception of data till 01/05/2023. We screened 4191 articles and included 3 clinical trials with published study results and 3 ongoing clinical trials. Results: In this systematic review, data on 2 chemotherapeutic agents Sotorasib (AMG510) and Adagrasib (MRTX849) which are Kras G12C inhibitors, are obtained from Code Break-100 and preliminary results of KRYSTAL-1 clinical trials, respectively. In these 2 clinical trials (N-48), all the patients had advanced pancreatic cancer with Kras G12C mutation and were previously treated with chemotherapy. 10 patients in Krystal-1 trial, who received adagrasib showed progression-free survival (PFS) of 6.6 months, disease control rate (DCR) of 100 % and partial response (PR) of 50%. 38 patients in the Code Break-100 trial, who received Sotorasib showed PFS of 4 months, DCR of 84.2% and PR of 21.1%. However, 50% of patients in the KRYSTAL-1 trial are still receiving treatment. Grade 3 /4 adverse events were seen in 21% and 16% of patients in the KRYSTAL-1 and Code Break-100 trial, respectively. Other Kras G12C inhibitors like D-1553, Sotorasib in combination with 2nd line chemotherapy are under investigation. Results of a clinical trial on anti KrasG12D siRNA done on locally advanced pancreatic cancer patients showed a median overall survival of 15.12 months with no dose limiting adverse events. A multinational randomized phase 2b clinical trial is ongoing for the evaluation of efficacy of siRNA based drug in combination with chemotherapy. Conclusions: Both Adagrasib and Sotorasib showed promising results in the pretreated Kras G12C pancreatic cancer patients with acceptable safety profile. Further exploration of these drugs and their combination with other chemotherapeutic agents is necessary. [Table: see text]

Aryl-hydrocarbon receptor agonist: A novel topical therapeutic approach for inflammatory skin diseases.

The broadening of novel therapeutic options for chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis (PSO), known to be associated with dysregulation of the immune response, systemic comorbidities and a reduced quality of life for patients and caretakers, offers better chances for long-lasting disease control.1, 2 Recent advances in clarifying the mechanisms that lead to the immune imbalance in both diseases indicate a predominant IL-23/IL-17A/IL36 pathway in psoriasis, and a predominant Th2 IL-4/IL-13, with the participation of IL-17 and IL-22 axis in atopic dermatitis.1, 2 The development of targeted-oriented therapies such as biologics and small molecule inhibitors (SMIs) changed the traditional management of such inflammatory conditions, therefore optimizing the standard of care in both diseases.1, 2 One of the new foci of targeted therapies for inflammatory skin diseases is the aryl-hydrocarbon receptor (AhR)/AhR-nuclear translocator (ARNT) system, which works as a sensor for exogenous and endogenous molecules. It is expressed in the skin and has a relevant role in the skin barrier maintenance, upregulating filaggrin and loricrin and enhancing epidermal differentiation. Furthermore, the AhR complex modulates the T-helper 17/22 and T regulatory axis, and some AHR ligands also exert a role in the neutralization of oxidative stress through the activation of the nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor and a ROS-scavenging structure.3 Bissonnette et al.4 present a review article on tapinarof (3,5-dihydroxy-4-isopropylstilbene), an AhR agonist from a historical perspective. His group has been working with this component since 2007, and the initial studies focused on psoriasis.5 Tapinarof 1% cream is a topical medication applied once daily, and the review shows the main outcomes of its use in clinical trials in patients with psoriasis and AD. The key point of this review indicates the profile of tapinarof in psoriasis and AD, as follows4: Psoriasis: A phase 2, single-centre clinical trial, showed a rapid start of action in topically applied bid tapinarof 1% group than vehicle. There was a 67.5% of improvement in PGA (physician global assessment) score to clear or almost clear against 4.8% in vehicle group at week 12 in psoriasis patients. In phase 2b (multicentre trial), tapinarof 0.5% and 1%, once or twice a day compared to vehicle was tested and reached the primary endpoints (PGA0/1) with 1%. The relevant finding of phase 2b was the sustained improvement during the 4-week follow-up. Subsequentially, the studies with tapinarof 1% once a day versus placebo including 1366 psoriasis patients, demonstrated an improvement of 35.4% and 40.2% for tapinarof group, versus 6% and 6.3% for vehicle in PGA score, and a PASI (Psoriasis Area Index Severity) 75 achievement in 36.1% in tapinarof group versus 10.2% for vehicle (at week 12). In the 1-year open-label extension study, the mean duration of effect remission (PGA0/1) off-therapy was 130.1 days. Atopic dermatitis: In one single-centre study, 34 AD patients randomized (1:1:1) to tapinarof 0.5%, 1% or vehicle were treated bid for 4 weeks, showing that 50% of AD patients in both treatment groups achieved an IGA of clear or almost clear compared to 8.3% for the vehicle group (at week 5). These findings were confirmed in a phase 2 study with AD patients. A randomized phase 2b study with 247 AD patients under bid or once daily application of tapinarof 0.5%, 1% or vehicle (12 weeks), assessing safety and efficacy in adolescents 12 years and older, indicated that at week 12, 53% of the AD patients with tapinarof 1% BID and 46% with once daily application achieved the primary endpoint (IGA of clear/almost clear with a 2-point decrease proportion) versus 24% and 28% for vehicle respectively. Tapinarof is currently undergoing phase 3 trials for AD patients in >2 years of age. The present study with topical tapinarof 1% cream in both psoriasis and AD opens unlimited field for more research and expansion of its use. One advantage for such medication is the long-lasting clearing of the skin lesions despite discontinuation, which could be very beneficial to patients with chronic conditions, impacting on the need for prolonged systemic therapies and therefore impacting on the patients' safety regarding adverse events and alleviating the economic impact of the disease. There are still more points to be addressed that may be clarified after more studies are conducted, such as whether the response to treatment will be effective and homogeneous depending on: stages of the disease (acute × chronic), age and ethnic/racial immune phenotypes (folliculitis5 is a clinical finding that may be more present in patients with AD of African descent, and was one of the reported initial adverse events of tapinarof). None declared. VA has participated in clinical trials for Lilli and Sanofi and as a consultant for Abbvie, Galderma and Leopharma. RLO has participated in clinical trials for Lilli, Sanofi and Amgen and as consultant for Bayer and Abbvie. Data sharing not applicable.

104 A Safety and Efficacy Study of NicaPlant® in Aneurysmal Subarachnoid Haemorrhage Patients Undergoing Aneurysm Clipping

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) has high morbidity and mortality. Secondary mechanisms of injury can aggravate the high negative impact. Cerebral vasospasm (CV) is one of the most relevant causes of this secondary injury. To improve the current treatment options, NicaPlant® was developed. METHODS: The trial was performed as an international randomized, controlled, single-blinded multicenter study. 40 Patients with WFNS grade 3 and 4 SAH undergoing surgical repair of their ruptured aneurysm were randomized to receive ten pellets of NicaPlant® (40 mg) plus standard of care or standard of care alone. The implants were administered immediately following clip ligation of the ruptured aneurysm in proximity to all the exposed cerebral blood vessels. The primary endpoint was the incidence of moderate to severe CV (day 8 ± 1). A blinded independent outcome accessor analyzed all imaging data. RESULTS: In the implant group, 20% (4/20) of patients reached the primary endpoint, compared to 58% (11/19) of patients in the control group (p = 0.024). Including mild CV, 75% of all patients in the control group developed CV compared to 30% in the implant group (p = 0.0129). 32% (6/19) of the patients in the control group developed new cerebral infarction, compared to 10% (2/20) in the implant group (p = 0.1273). Endovascular rescue therapy was performed in 10% of the patients in the implant group compared to 58% in the control group (p = 0.002). 4 subjects (20%) in the control group experienced Treatment-emergent adverse events (TEAE), compared with none in the active group. CONCLUSIONS: In this prospective randomized multicenter Phase 2b trial, we could demonstrate the safety and efficacy of NicaPlant® implants in preventing CV in patients with SAH.

Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

A Real World Experience of Combined Treatment with Romidepsin and Azacitidine in Patients with Peripheral T-Cell Lymphoma - a Bridge to Transplant and an Effective Salvage for the Unfit

Introduction Patients with peripheral T cell lymphoma (PTCL) lack good treatment options, particularly in the relapsed and refractory setting (Mak V et al. J Clin Oncol 2013). The development of the targeted therapies in PTCL has been lagging behind those developed for B cell lymphomas. Our work suggested that combination of epigenetic therapies could be a safe and effective approach in PTCL, particularly in T cell lymphomas with follicular helper phenotype (Marchi E et al. Br. J Haematol 2015; O'Connor AO et al; Blood 2019; Falchi L et al. Blood 2020). This could be explained by the presence of recurrent mutations in epigenetic factors, including Ten-Eleven Translocation-2 (TET2), DNA methyl transferase-3A (DNMT3A), and isocitrate dehydrogenase-2 (IDH2). that specifically clusters in PTCL (Couronné L. et al. N Eng J Med 2012; Lemonnier F et al. Blood 2012). Despite these observations, a direct link between presence of the mutations and sensitivity to treatment remain to be established. Objectives To evaluate the merits of romidepsin plus azacitidine in patients with PTCL when administered in a 'real-world’ scenario (both subcutaneous and oral azacytidine). Our phase 2 study of oral azacitidine in combination with romidepsin showed remarkable results and we wanted to evaluate the efficacy of these two drugs in patients who were not enrolled on a clinical study for following reasons: 1) Rarity of PTCL prevents wide availability of clinical studies for this patient population; 2) Enrollment criteria, including performance status, prevent enrollment of all patients who are too frail but could possibly benefit from this treatment; 3) Second synchronous or recent malignancies. Methods We retrospectively identified PTCL patients that were treated with azacitidine and romidepsin outside of a clinical trial based upon queries regarding off study use. The study was reviewed and approved by each Medical Center Institutional Review Board. We have identified 26 patients world-wide and these patients were treated using 4 different schedules: Schedule A: azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 14 mg/m2 on day 1, 8 and 15 of a 28 day cycle (total of 7 patients); Schedule B: azacitidine 75mg/m2 s.c. on days 1-5, romidepsin 14 mg/m2 on day 8, 15 and 22 of a 35 day cycle; Schedule C (6 patients): azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 12-14 mg/m2 on day 8, 15 and 22 of a 28 day cycle (6 patients); and Schedule D (as per Falchi L. et al. Blood 2020, 7 patients). Results In our retrospective analysis we have identified 18 patients who had angioimmunoblastic lymphoma (AITL), 2 with adult T-cell leukemia/lymphoma (ATLL), 3 with TFH PTCL, 1 with PTCL-NOS and 2 with composite lymphoma (TFH PTCL with diffuse large B cell lymphoma and ALK- ALCL with FL). Twelve of the 26 patients had next generation sequencing performed. Most common mutations found were those of TET2 (8 pts), RHOA (4pts), IDH2 (3pts) and DNMT3A (2 pts). Among these 26 patients, overall response rate (ORR) was 73% and the complete response rate (CR) was 53%. Median number of cycles was 3.5 (range 1-12). Treatment was well tolerated and notable adverse effects included nausea, fatigue, rash, neutropenia and thrombocytopenia. One patient experienced febrile neutropenia while another had pulmonary infiltrates (drug toxicity vs. infection). Thrombocytopenia was the most common reason for dose reduction of romidepsin (to 12mg/m2) or its omission on day 8, 15 or 22. Median OS and PFS were not reached and 13.3 months respectively (Figure 1). Median DOR was not reached. In 8 patients, azacitidine and romidepsin were used to achieve remission prior to stem cell transplant (1 auto, 7 allo), with all 7 patients were in CR at their last disease assessment. One patient died of transplant related mortality 8 months after his allogeneic stem cell transplant. Conclusion Subcutaneous azacitidine and romidepsin administered in a 'real-world’ situation is highly effective in patients with relapsed PTCL with tolerable toxicity, and can be used to successfully bridge patients to stem cell transplant and to treat frail patients that would not be candidate for enrollment in clinical trials.. Notably, the efficacy was similar to the one reported on a clinical study with oral azacitidine and romidepsin. A randomized phase 2B trial of romidepsin and oral azacitidine versus investigator's choice in patients with R/R PTCL is currently ongoing and open to enrollment (NCT04747236). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ruxolitinib Versus Best Available Therapy in Patients with Essential Thrombocythemia: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Ruxolitinib Versus Best Available Therapy in Patients with Essential Thrombocythemia: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial

Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50mg, 100/50mg, 30mg, or 10mg) or placebo for 24weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24. A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50mg groups with (-21.2 vs 2.1; P<.001) or without (-18.5 vs 2.1; P<.001) a loading dose and ritlecitinib 30mg group (-14.6 vs 2.1; P=.01). Accelerated improvement was observed after treatment with ritlecitinib 200/50mg in the extension period (n=187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment. Patients with stable vitiligo only were excluded. Oral ritlecitinib was effective and well tolerated over 48weeks in patients with active nonsegmental vitiligo.

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus

GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. One hundred forty-seven patients received placebo (n= 36) or linerixibat (once daily: 20 mg, n= 16; 90 mg, n= 23; 180 mg, n= 27; twice daily: 40 mg, n= 23; 90 mg, n= 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P= .0424), 40 mg twice daily (P= .0105), and 90 mg twice daily (P= .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P= .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. gov ID: NCT02966834.

A phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer (mCRPC).

5016 Background: Intravenous (IV) docetaxel and oral prednisone is a standard of care regimen in patients (pts) with mCRPC. ModraDoc006 is an oral formulation of docetaxel. To enhance bioavailability of ModraDoc006, it is co-administered with ritonavir (/r). The ModraDoc006 and ritonavir combination is active in multiple docetaxel and cabazitaxel-resistant prostate cancer cell-lines The oral combination (ModraDoc006/r) was compared to IV docetaxel in a randomized phase 2b study in pts with mCRPC evaluating two doses of ModraDoc006/r (30-20/200-100 mg and 20-20/200-100 mg). Data on outcomes in the larger cohort, receiving the lower dose, are being presented. Methods: Eligible pts had mCRPC, performance status of 0-1 and no prior chemotherapy for mCRPC. Sixty-two pts were enrolled in open label 1:1 randomized study comparing ModraDoc006/r 20-20 mg combined with 200-100 mg ritonavir in a bi-daily weekly schedule (“20-20/200-100 mg”), with IV docetaxel 75 mg/m2 in 21-day cycles. All pts received 5 mg oral prednisone twice daily. Primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives included ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Results: 31 pts were enrolled on IV docetaxel 75 mg/m2 and 31 on ModraDoc006/r 20-20/200-100 mg. Of these, 57 were included in the analysis for rPFS, and 32 pts with measurable disease were included in the ORR analysis. Median PSA was 46 (range 1 to 1460 ng/ml). Prior therapy with enzalutamide in 8 pts, abiraterone in 10 pts. ModraDoc006/r was better tolerated with 0% all grades neutropenia and anemia, as compared to 26% (19% ≥G3) and 16% respectively on IV docetaxel. Neuropathy was significantly reduced at 9.7% G1 only on ModraDoc006/r vs 9.7% G1 and 19.4% G2 on IV docetaxel, whereas alopecia was reduced to 16.1% G1 and 6.5% G2 on ModraDoc006/r vs. 22.6% G1 and 19.4% G2 on IV docetaxel. GI toxicities were broadly comparable with diarrhea 32% (3% ≥G3) vs 29%, nausea 29% vs 13% and stomatitis 3% (G3) vs 13% (3% ≥G3), respectively. Conclusions: ModraDoc006/r demonstrated a favorable safety profile and comparable efficacy to IV docetaxel in pts with mCRPC, thus providing a compelling rationale for conduct of an expanded pivotal program. A key clinical program focus is the comparison of ModraDoc006/r to best available therapy in refractory mCRPC. Studies of ModraDoc006/r in other malignancies are also in active development. Clinical trial information: NCT04028388. [Table: see text]

Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study

Background: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions. Objective and Methods: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups. Results: The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions (p = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged. Conclusion: Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS. Trial registration: CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18

Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study.

OBJECTIVECotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for nonalcoholic steatohepatitis (NASH) and chronic kidney disease with type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes.RESEARCH DESIGN AND METHODSIn this phase 2b study, 834 adults with BMI ≥25 kg/m2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A1c [HbA1c] of 7.0%–10.5% [53–91 mmol/mol]) were randomized to double-blind cotadutide 100 μg (n = 100), 200 μg (n = 256), or 300 μg (n = 256); placebo (n = 110); or open-label liraglutide 1.8 mg (n = 110)—all administered subcutaneously. Coprimary end points were changes in HbA1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed.RESULTSCotadutide significantly decreased HbA1c and body weight at weeks 14 and 54 versus placebo (all P < 0.001). Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with cotadutide 300 μg versus placebo, but not with liraglutide. Weight loss with cotadutide 200 μg was similar to that with liraglutide 1.8 mg and greater with cotadutide 300 μg versus liraglutide 1.8 mg. The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time.CONCLUSIONSCotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH.

A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma.

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

Phentolamine Mesylate Ophthalmic Solution Provides Lasting Pupil Modulation and Improves Near Visual Acuity in Presbyopic Glaucoma Patients in a Randomized Phase 2b Clinical Trial.

PurposePhentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population.Patients and MethodsIn this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia.ResultsUse of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo (P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥1 line of improvement in photopic DCNVA at day 8 (P = 0.0018), day 15 (P = 0.0072), and day 16 (P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo.ConclusionAlthough mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies.