Summary Background Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAFV600E -mutant or BRAFV600K -mutant advanced melanoma; ...however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF -mutant melanoma. Methods We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAFV600E -mutant or BRAFV600K -mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomised trials. Patients with untreated brain metastases were not permitted to enrol in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analysed for association with progression-free survival and overall survival using univariate and multivariate analyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analysed factors identified after baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov : BRF113220, number NCT01072175 ; COMBI-d, number NCT01584648 ; COMBI-v, number NCT01597908. Findings 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0−48·0, IQR 10·1−24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months 95% CI 9·7−12·9), median overall survival (25·6 months 23·1−34·3), 1-year progression-free survival (48% 44–52) and overall survival (74% 71–78), and 2-year progression-free survival (30% 26–34) and overall survival (53% 49–57) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% 95% CI 62–74) and overall survival (90% 87–94) and 2-year progression-free survival (46% 40–54) and overall survival (75% 70–81), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% 3–19) and overall survival (40% 29–55) and 2-year progression-free survival (2% 0–13) and overall survival (7% 3–19). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months 95% CI 7·9−12·0) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months 3·5−4·9). Interpretation Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets. Funding Novartis.
BackgroundDose-limiting toxicity (DLT) due to systemic CD40 activation and peripheral target-mediated drug disposition are major challenges in clinical development of CD40 agonists. MP0317, a ...CD40-agonistic DARPin (designed ankyrin repeat protein), is exclusively active in the presence of fibroblast activation protein (FAP) expressed by cancer-associated fibroblasts in the tumor microenvironment (TME). This mode of action enables tumor-localized CD40 activation, while reducing systemic toxicity.MethodsThis ongoing Phase 1, multicenter, open-label, dose-escalation study aims to establish safety/tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of MP0317 monotherapy (NCT05098405). The dose-escalation scheme uses an adaptive Bayesian logistic regression model guided by the escalation with overdose control principle to determine the recommended dose. Eligible adult patients with selected advanced solid tumors (based on anticipated FAP expression) are enrolled into 9 sequentially-escalating dose cohorts of MP0317 (0.03–10 mg/kg), administered IV 3-weekly (Q3W) or 1-weekly (Q1W) until disease progression or unacceptable toxicity. The study was approved by the Dutch and French Ethics Boards.ResultsAs of data cut-off (02 May 2023), 36 patients received ≥1 MP0317 dose across 8 cohorts, including 19 women (53%) and 17 men (47%). The median age at enrollment was 63 years (range 35–79) and patients received a median number of 3.5 prior treatments (range 1–13). Colorectal cancer was the most frequent tumor type (11 patients, 31%). One patient experienced a DLT (asymptomatic Grade 3 elevation of alanine and aspartate aminotransferases), at the highest planned dose of MP0317 (10 mg/kg Q3W). Grade 2 infusion-related reaction was the most frequently observed adverse reaction (7 patients, 19%), followed by Grade ≤2 fatigue, nausea and vomiting in 9, 6, and 4 patients, respectively. One patient achieved unconfirmed partial response, and stable disease was observed in 5 patients. Paired tumor biopsies confirmed colocalization of MP0317 with FAP and CD40. MP0317 detection in tumor biopsies was associated with an increase in abundance of antigen-presenting cells (dendritic cells, B cells and plasma cells) and IFNγ signature in the TME. Increases in CXCL10 serum levels post-MP0317 treatment support these findings.ConclusionsThese data of 36 patients, dosed across 8 dose levels (0.03–10 mg/kg, Q3W and Q1W schedules), confirmed a favorable safety profile of MP0317 monotherapy with limited systemic inflammation compared to other CD40 agonists. Analysis of paired tumor biopsies and peripheral biomarkers provided evidence of target occupancy and pharmacodynamic modulation in the TME, consistent with tumor-localized CD40 activation. These data support continued clinical evaluation of MP0317, including combination studies.Trial RegistrationThis study is registered at ClinicalTrials.gov: NCT05098405Ethics ApprovalThe study was approved by the Dutch and French Ethics Boards.
2573 Background: Major challenges of the clinical development of CD40 agonists are toxicity due to systemic CD40 activation and peripheral target-mediated drug disposition. MP0317, a CD40 agonist ...DARPin (designed ankyrin repeat protein), is exclusively activated by binding to fibroblast activation protein (FAP) on cancer-associated fibroblasts. This enables local CD40 activation in the tumor microenvironment (TME) and reduces systemic toxicity. Methods: This Phase 1, multicenter, open-label, dose-escalation study assessed safety/tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of MP0317 monotherapy (NCT05098405; data cut-off 15 Jan 2024). Eligible adults with selected advanced solid tumors (based on predicted FAP expression) were enrolled into 9 dose-escalation cohorts of MP0317 0.03–10 mg/kg administered IV 3-weekly (Q3W) or weekly (Q1W) until disease progression or unacceptable toxicity. Blood biomarkers were analyzed by immuno-assays and flow cytometry, and paired tumor biopsies by RNA sequencing and immunofluorescence. Results: Dose-escalation enrolment is complete and 46 patients received ≥1 MP0317 dose, including 24 women (52%) and 22 men (48%). Median age at enrolment was 63 years (range 35–79). Patients received a median of 4 prior treatment lines (range 1–13). Colorectal cancer was the most frequent tumor type (12 patients, 26%). MP0317 maximum tolerated dose was not reached; only one patient experienced a dose-limiting toxicity (asymptomatic Grade 3 alanine and aspartate aminotransferases elevation), at the highest planned dose of MP0317 (10 mg/kg Q3W). Grade ≤2 fatigue was the most frequent adverse reaction (15 patients, 30%), followed by Grade ≤2 infusion-related reaction, nausea and anorexia in 8, 7, and 5 patients, respectively. One patient achieved unconfirmed partial response, and stable disease was observed in 11 patients (24%). Serum PK data showed MP0317’s half-life extended properties and sustained exposure at higher doses. Paired tumor biopsies confirmed the colocalization of MP0317 with FAP and CD40. MP0317 detection in tumor biopsies at doses ≥1.5 mg/kg was associated with an increase in antigen-presenting (dendritic and B cells), plasma and T follicular helper cell abundance, as well as enhanced dendritic cell maturation and IFNγ production in the TME. CXCL10 serum level increases post MP0317 treatment supported these findings. Only minor changes were seen in pro-inflammatory cytokines. Conclusions: MP0317 had a favorable safety profile in 46 patients across all 9 dose-escalation cohorts exploring Q3W and Q1W regimens. Doses ≥1.5 mg/kg showed evidence of pharmacodynamic TME modulation, indicating tumor-localized CD40 activation. The data support further clinical evaluation of MP0317 including combination with complementary anticancer therapies. Clinical trial information: NCT05098405 .
BACKGROUND: The development of targeted immunotherapy for acute myeloid leukemia (AML) is challenging due to the clonal heterogeneity of the disease and the lack of single AML-specific target ...antigens. MP0533 is a multi-specific, half-life extended CD3-engaging DARPin (Designed Ankyrin Repeat Protein). It simultaneously targets CD33, CD123, and CD70, thereby enabling avidity-driven T cell-mediated killing of leukemic stem cells (LSCs) and malignant blast cells known to co-express these targets. MP0533's affinity to each target is tuned to preferentially kill malignant cells which co-express at least two of these three antigens, while preserving a therapeutic window towards healthy cells. MP0533 was shown to induce a tumor-specific endogenous T-cell response in ex vivo samples from AML patients and led to T-cell-mediated eradication of tumors in AML xenograft mouse models, with limited cytokine release or other serious adverse reactions (Bianchi et al., Blood 2022;140Suppl 1:2251-2). Herein, we present early observations of the first three MP0533 dose-escalation regimens (DR) of the ongoing first-in-human, multicenter, single-arm, open-label, phase 1/2a study. METHODS: The objectives of this ongoing trial are to evaluate the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics, as well as preliminary antileukemic activity of MP0533 monotherapy in patients with relapsed/refractory (R/R) AML or myelodysplastic syndrome (MDS)/AML (NCT05673057). Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of ≥12 weeks are eligible. Up to 45 patients will be enrolled in the dose-escalation part of the trial. Patients receive MP0533 once per week starting at day 15 after a stepwise dose increase on days 1, 5, and 8, and until disease progression or unacceptable toxicity. One cycle corresponds to 28 days. DR escalation of MP0533 is guided by two Bayesian logistic regression models estimating the joint probability of cytokine release syndrome (CRS) and non-CRS dose-limiting toxicities (DLTs). Bone marrow examinations are performed at weeks 4, 8, and 12. Responses are determined using 2022 European LeukemiaNet (ELN) criteria with an assessment of hematologic improvement. Treatment-emergent adverse events (TEAEs) are assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. RESULTS: As of data cut-off (20 July 2023), 5 patients received ≥5 infusions of MP0533 across 3 DRs preceded by step-up dosing (1 patient each at DR 1 and DR 2, respectively, and 3 patients at DR 3), including 2 women and 3 men. The median age at enrollment was 79 years (range 68-81). All patients had adverse risk mutations. Patients received a median number of 1 prior antileukemic therapy line (range 1-2) and on average 2 cycles of MP0533 treatment (range 1-3). To date, one patient with a TP53 mutation achieved a morphologic leukemia-free state after 8 weeks and complete remission with incomplete hematologic recovery (CRi) after 12 weeks of treatment with DR 3. No DLTs have been observed in any DR so far. TEAEs considered to be related to MP0533 were Grade 2 infusion-related reaction (2 patients), Grade 1 CRS (2 patients), and Grade 1 diarrhea and fatigue (1 patient). No Grade ≥3 drug-related TEAEs were reported. The reported TEAEs (Figure) reflected the patients' disease course. Preliminary PK results up to DR 3 confirmed that all patients were exposed to MP0533 and exposure levels were broadly aligned with PK/PD model predictions of MP0533 in serum. CONCLUSION: The results of this ongoing phase 1/2a study indicated an acceptable safety profile of MP0533 monotherapy in 5 patients up to DR 3 with weekly infusions. Preliminary response data are encouraging, with one response observed in 1 of 2 patients evaluable for response in DR 3 to date.
Aims
This study aimed to assess safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of ensovibep, a designed ankyrin repeat protein antiviral being evaluated as a COVID‐19 ...treatment, in healthy volunteers in a first‐in‐human ascending single‐dose study.
Methods
Subjects were dosed intravenously, in a randomized double‐blinded manner, with either ensovibep at 3, 9 or 20 mg/kg or with placebo, and followed until Day 100. PK and safety were assessed throughout the study duration. Immunogenicity and PD via viral neutralization in serum were also assessed.
Results
All adverse events were of mild to moderate severity, and no serious adverse events were observed. One subject who received the 20‐mg/kg dose presented with moderate hypersensitivity vasculitis 3 weeks after infusion, which fully resolved using standard procedures. In most subjects ensovibep showed expected mono‐exponential decline with a half‐life of around 2 weeks. Anti‐drug antibodies were detected in 15 of 17 subjects, with the earliest onset detected on Day 29. Viral neutralization assays on subject serum showed effective viral neutralization over the first 3 weeks following dosing with titre values in a dose dependent manner.
Conclusion
Ensovibep proved safe in this first‐in‐human safety study and exhibited PK and PD parameters consistent with the expected treatment period required for acute COVID‐19 infection.
Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.
To evaluate whether levels ...of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.
Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.
114 centers in 10 countries.
Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.
Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.
Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 CI, 3.41 to 7.50) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 CI, 0.45 to 0.57), with subhazard ratios similar across all levels of baseline pulmonary severity.
Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.
Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.
U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.
This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as ...maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN).
Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy.
Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm.
Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.
Abstract Background This randomised Phase II study assessed the activity and safety of concurrent chemoradiotherapy (CRT) and lapatinib followed by maintenance treatment in locally advanced, ...unresected stage III/IVA/IVB head and neck cancer. Patients and methods Patients were randomised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib. Treatment continued until disease progression or study withdrawal. Primary end-point was complete response rate (CRR) by independent review 6 months post-CRT. Results Sixty-seven patients (median age 56 years; 97% Eastern Cooperative Oncology Group performance status ⩽1; 82% stage IV) were recruited. CRT dose intensities were unaffected by lapatinib: median radiation dose 70 Gy (lapatinib, placebo), duration 49 (lapatinib) and 50 days (placebo); median cisplatin dose 260 mg/m2 (lapatinib) and 280 mg/m2 (placebo). Lapatinib combined with CRT was well-tolerated. Grade 3/4 toxicities during CRT were balanced between arms, with the exception of an excess of grade 3 diarrhoea (6% versus 0%) and rash (9% versus 3%) and two grade 4 cardiac events in the lapatinib arm. CRR at 6 months post-CRT was 53% with lapatinib versus 36% with placebo in the intent-to-treat population. The progression-free survival (PFS) and overall survival rates at 18 months were 55% versus 41% and 68% versus 57% for the lapatinib and placebo arms, respectively. The difference between study arms was greatest in p16-negative disease (median PFS >20.4 months lapatinib versus 10.9 placebo). Conclusion Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease.
2584
Background: CD40 is a master switch for both innate and adaptive immune systems. The clinical development of CD40 agonists has been hampered by dose-limiting toxicity (DLT) due to systemic CD40 ...activation and peripheral target-mediated drug disposition (TMDD). MP0317 is a CD40-agonistic DARPin (designed ankyrin repeat protein), developed to reduce systemic toxicity. MP0317 is exclusively active in the presence of fibroblast activating protein (FAP) expressed by cancer associated fibroblasts in the tumor microenvironment. This allows reaching serum levels that overcome the TMDD and have the potential to deliver sustained and tumor-localized CD40 activation. Ongoing clinical testing aims at establishing its safety/tolerability profile, PK/PD characteristics, and a recommended dose for combination therapy. Methods: NCT05098405 is a Phase 1, multicenter, open label, dose escalation study followed by a safety expansion part in adult patients with advanced solid tumors. The dose escalation scheme uses an adaptive Bayesian logistic regression model with overdose control. Peripheral blood biomarkers are analyzed by immuno-assays and flow cytometry, and baseline and on-treatment tumor biopsies are characterized by RNA sequencing and immunofluorescence. Eligible patients are enrolled into 9 sequentially escalating dose cohorts of MP0317 (0.03-10 mg/kg), administered IV 3-weekly (Q3W) or 1-weekly (Q1W) until disease progression or unacceptable toxicity. Results: At submission, 23 patients across 6 cohorts completed the study, with no DLT observed. Patient enrolling in higher dose cohorts is ongoing. The most frequent AE was grade 2 infusion related reaction in 5 patients. The 23 patients received ≥2 (range 2-8) doses (range 0.03 – 3 mg/kg) of MP0317 across five Q3W and one Q1W cohorts and completed the 28-day DLT period. PK data confirmed all patients were exposed to MP0317 with broadly dose-dependent Cmax and no sign of accumulation. PD data was derived from patients dosed with 0.03 – 3 mg/kg. Soluble biomarkers (sFAP and sCD40) showed target engagement in periphery with signs of FAP saturation at ≥0.5 mg/kg. Colocalization of MP0317 with FAP and CD40 in the tumor was confirmed in 4 out of 8 evaluable paired tumor biopsies. Whole transcriptome and gene set enrichment analyses showed an upregulation of genes related to B-cell trafficking (CXCL3, CXCR5, CCR6, CCL20) upon treatment. Transient increase of IFNg-induced chemokines (CXCL9, CXCL10) was observed, whereas the pro-inflammatory cytokines (TNFa, IL-2, IL-6, IL-8) were not upregulated. Conclusions: Clinical data and the lack of pro-inflammatory circulating cytokines confirm MP0317 is safe and well-tolerated, while analysis of paired pre- and on-treatment tumor biopsies suggests early evidence of tumor-localized CD40 activation. The current data enables further evaluation in a combination setting. Clinical trial information: NCT05098405 .
Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.
To investigate if ensovibep, in addition to ...remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.
Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).
Multinational, multicenter trial.
Adults hospitalized with COVID-19.
Intravenous ensovibep, 600 mg, or placebo.
Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.
An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (
= 247) or placebo (
= 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30;
= 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio sHR, 1.06 CI, 0.88 to 1.28; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 CI, 0.77 to 1.47; HR < 1 would favor ensovibep).
The trial was prematurely stopped because of futility, limiting power for the primary outcome.
Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.
National Institutes of Health.
