Intratumoral Delivery of MDNA55, an Interleukin-4 Receptor Targeted Immunotherapy, by MRI-Guided Convective Delivery for the Treatment of Recurrent Glioblastoma

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Higher Doses of Subcutaneous IgG Reduce Resource Utilization in Patients with Primary Immunodeficiency

The recommended dose of IgG in primary immunodeficiency (PID) has been increasing since its first use. This study aimed to determine if higher subcutaneous IgG doses resulted in improved patient outcomes by comparing results from two parallel clinical studies with similar design. One patient cohort received subcutaneous IgG doses that were 1.5 times higher than their previous intravenous doses (mean 213 mg/kg/week), whereas the other cohort received doses identical to previous subcutaneous or intravenous doses (mean 120 mg/kg/week). While neither cohort had any serious infections, the cohort maintained on higher mean IgG dose had significantly lower rates of non-serious infections (2.76 vs. 5.18 episodes/year, P < 0.0001), hospitalization (0.20 vs. 3.48 days/year, P < 0.0001), antibiotic use (48.50 vs. 72.75 days/year, P < 0.001), and missed work/school activity (2.10 vs. 8.00 days/year, P < 0.001). The higher-dose cohort had lower health care utilization and improved indices of well being compared to the cohort treated with traditional IgG doses

Multi-parametric MRI as supplement to mRANO criteria for response assessment to MDNA55 in adults with recurrent or progressive glioblastoma.

e13559 Background: Modified response assessment in neuro-oncology (mRANO) criteria are widely used in GBM but seem insufficient to capture Pseudoprogression (PsP), which occurs due to extensive inflammatory infiltration, increased vascular permeability, tumor necrosis and edema. mRANO criteria recommend volumetric response evaluation using contrast-enhanced T1 subtraction maps for identifying PsP. Our approach incorporates multi-parametric MRI biomarkers to unravel the true PsP from recurrence or distinguish Pseudo Response (PsR) - following anti-VEGF agents - from delayed (immuno)response. Methods: Multiple time-points MRI (18-24h after convection-enhance delivery of the anti-IL4-R agent MDNA55, then at 30-day intervals) was utilized to determine response. Multi-parametric MRI biomarkers analyzed included (1) 3D-FLAIR-T2-based tumor volume assessment reflecting edema, necrosis and tumor infiltration; (2) 3D-gadolinium-enhanced-based tumor volume estimation reflecting active tumor infiltration, neo-angiogenesis and disrupted blood brain barrier; (3) Dynamic susceptibility contrast-based relative cerebral blood volume (rCBV) measurements for estimation of the vascular tumour properties; and (4) Diffusion weighted imaging – Apparent diffusion coefficient measurements that assess interstitial edema, tumor cellularity and ischemic injury. Results: We demonstrate similar imaging phenotypes on conventional FLAIR-T2- and enhanced T1- MR images among different disease states (PsP vs true progression, PsR vs and immuno-response) and describe the perfusion and diffusion MRI biomarkers that improve response staging including PsP masking true progression, PsP masking clinical response, early progression with delayed response, and differentiation between true and PsR. The results are compared with the mRANO-based assessments for concurrence. Conclusions: Incorporating multi-parametric MRI measurements to determine the complex underlying tissue processes enables a better assessment of PsP, PsR and delayed tumour response, and can supplement mRANO-based response assessments in GBM patients undergoing novel immunotherapies. </jats:p

Long-term efficacy, safety, and tolerability of Hizentra® for treatment of primary immunodeficiency disease

AbstractHizentra® (20% subcutaneous immunoglobulin [SCIG]) was administered to subjects with primary immunodeficiency disease in two extension studies in the EU and US to assess long-term efficacy and tolerability. Subjects (aged 4–69years) were treated for 148weeks in the EU (N=40; 5405 infusions) and 87weeks in the US (N=21; 1735 infusions). Weekly doses were 116.0mg/kg (EU) and 193.2mg/kg (US); IgG levels were 7.97g/L (EU) and 11.98g/L (US). Annualized rates of serious bacterial infections were 0.05infections/subject/year (EU) and 0.06infections/subject/year (US). Rates of any infection were 3.33infections/subject/year (EU) and 2.38infections/subject/year (US). The rate of bronchopulmonary infections was higher in the EU study. No treatment-related serious AEs occurred; no subject discontinued because of treatment-related AEs. Self-administered Hizentra afforded sustained effective protection from infections and favorable tolerability during an extended treatment period of up to 3years

CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL

Abstract BACKGROUND Drug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing results of a single-arm Phase 2b trial of intratumoral delivery of MDNA55 (an interleukin-4 receptor targeted fusion protein) to an external control arm, we sought early efficacy insights and consideration by the FDA of incorporating an ECA in a Phase 3 registrational trial. METHODS Using propensity score weighting, we compared rGBM patients from the Phase 2b trial (NCT02858895) (2017-2019) to patients from rGBM registries who had received standard of care therapies (2011-2019) and met eligibility requirements. Propensity scores were estimated using a logistic regression model with 11 covariates. We compared the propensity score weighted groups according to demographic and disease attributes before and after weighting and compared overall survival between the two groups. RESULTS Through propensity score weighting, 43 (98%, 43/44) MDNA55 patients and 40.80 weighted ECA patients (from 62 unweighted registry patients) were identified for comparison. MDNA55 and ECA patients were balanced on all baseline characteristics (i.e., standardized mean difference ≤ 0.15). Compared to ECA patients, MDNA55 patients had a 37% lower hazard of death (hazard ratio 0.63, 95% confidence interval: 0.39,1.02). CONCLUSION In advance of a Phase 3 trial, comparison of Phase 2b trial results to an ECA suggests that MDNA55 may be efficacious in rGBM. In view of the known challenges associated with drug development for rGBM, these results provided a proof-of-concept for the design of a novel hybrid Phase 3 trial. This planned Phase 3 trial incorporates propensity score weighting to create a composite hybrid randomized and external control arm, an approach preferred by the FDA over full replacement of a randomized control with an external control. </jats:sec