scholarly journals CTIM-13. CLINICAL EFFICACY OF MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, IN RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii35-ii35
Author(s):  
John Sampson ◽  
Achal Achrol ◽  
Manish Aghi ◽  
Krystof Bankiewiecz ◽  
Martin Bexon ◽  
...  
Keyword(s):  
De Novo ◽  
Interleukin 4 ◽  
Tumor Control ◽  
High Dose ◽  
Synthetic Control ◽  
Patient Registries ◽  
Open Label ◽  
Convection Enhanced Delivery ◽  
Poor Outcomes ◽  
Interleukin 4 Receptor

Abstract BACKGROUND MDNA55 is an IL4R-targeted toxin in development for GBM, a universally fatal disease. IL4R is over-expressed in GBM, the tumor microenvironment, and high expression is associated with poor outcomes in GBM. METHOD MDNA55-05 is an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in rGBM patients at 1st or 2nd recurrence with an aggressive form of GBM (de novo GBM, IDH wild-type, not-resectable at recurrence, ~ 50% expressing high levels of IL4R). Primary endpoint is mOS, secondary endpoint includes impact of IL4R status on mOS. A Synthetic Control Arm (SCA) served as an external comparator constructed from patient registries at neurosurgery centers under IRB-approved protocols. Propensity score weighting corrected for imbalances in baseline characteristics between the two groups. RESULTS MDNA55 showed an acceptable safety profile at doses up to 240μg. In all evaluable subjects (n=44) mOS was 11.6 and OS-12 was 46%. A sub-population (n=32) consisting of all IL4RHigh subjects + only IL4RLow subjects treated with high dose (median 180µg) showed most benefit: mOS is 15 months, OS-12 is 55%. Tumor control, assessed by mRANO criteria, was seen in 81% (26/32) of this sub-population, including those that had pseudo-progression (15/26). In these subjects, tumor control was associated with longer mPFS (4.7 months) and mOS (15.0 months) than those with progressive disease (mPFS 1.0 month, mOS 7.7 months). Comparison against the SCA demonstrated > 100% increase in mOS: 15.7 months vs 7.2 months (HR 0.52, 95% CI 0.30, 0.91). CONCLUSIONS MDNA55 demonstrates improved survival and tumor control in this study design and has potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. There are no approved therapies for rGBM that can extend survival by 50%; the potential for MDNA55 to extend survival by > 100% is promising for this devastating disease.

MDNA55 survival in recurrent glioblastoma (rGBM) patients expressing the interleukin-4 receptor (IL4R) as compared to a matched synthetic control.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2513-2513
Author(s):  
John H. Sampson ◽  
Achal Achrol ◽  
Manish K. Aghi ◽  
Krystof Bankiewicz ◽  
Martin Bexon ◽  
...  
Keyword(s):  
De Novo ◽  
Interleukin 4 ◽  
Tissue Banks ◽  
Synthetic Control ◽  
Single Treatment ◽  
Patient Registries ◽  
Open Label ◽  
Convection Enhanced Delivery ◽  
Pseudomonas Exotoxin A ◽  
The Impact

2513 Background: MDNA55 is an engineered IL-4 fused to pseudomonas exotoxin A being developed for GBM, an aggressive, universally fatal disease. No curative therapy exists and 75% of patients are not eligible for resection at recurrence. MDNA55 targets IL4R overexpressed in GBM, the immunosuppressive tumor microenvironment, and high expression is associated with poor survival outcomes in GBM. A Ph 2b trial of MDNA55 was completed in rGBM using convection-enhanced delivery to bypass the BBB. Here we report results from the Ph 2b trial and comparison against a matched Synthetic Control Arm (SCA). Methods: MDNA55-05 is an open-label, single-arm study of intratumoral delivery of ≤ 240 μg MDNA55 as a single treatment via ≤ 4 catheters in de novo GBM without IDH1/2 mutation at 1st or 2nd recurrence not eligible for resection, tumors ≤ 4 cm, KPS ≥ 70. IL4R expression in GBM tissues was determined by H-Score using a validated IHC assay. 1o endpoint is median overall survival (mOS); 2o endpoint includes the impact of IL4R status on mOS. An eligibility-matched SCA was identified retrospectively from patient registries at major neurosurgery centers with access to GBM tumor tissue banks under IRB-approved protocols. Results: 44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide. Conclusions: MDNA55 subjects represent a difficult to treat population ( de novo GBM, IDH wild-type, not eligible for surgery at recurrence). Single treatment with MDNA55 prolongs survival by nearly 10 months in a subset of rGBM expressing high levels of IL4R when compared to a matched SCA, providing an unprecedented outcome for this highly lethal disease. Clinical trial information: NCT02858895 .

CTIM-28. MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, FOR RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi56-vi57
Author(s):  
John Sampson ◽  
Achal Singh Achrol ◽  
Manish K Aghi ◽  
Krystof Bankiewiecz ◽  
Martin Bexon ◽  
...  
Keyword(s):  
De Novo ◽  
Symptom Control ◽  
Recurrent Glioblastoma ◽  
Interleukin 4 ◽  
External Control ◽  
High Dose ◽  
Open Label ◽  
Convection Enhanced Delivery ◽  
High Concentrations ◽  
Dose Volumes

Abstract BACKGROUND MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment. METHOD MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied. RESULTS MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively. CONCLUSIONS MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.

scholarly journals ATIM-30. COMBATING RECURRENT GLIOBLASTOMA WITH MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, THROUGH MRI-GUIDED CONVECTIVE DELIVERY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi8-vi8
Author(s):  
John Sampson ◽  
Achal Singh Achrol ◽  
Manish Aghi ◽  
Krystof Bankiewicz ◽  
Steven Brem ◽  
...  
Keyword(s):  
Disease Control ◽  
Cerebral Blood Volume ◽  
Clinical Decision Making ◽  
Objective Response ◽  
Safety Data ◽  
Clinical Decision ◽  
Recurrent Glioblastoma ◽  
Interleukin 4 ◽  
High Dose ◽  
Convection Enhanced Delivery

Abstract MDNA55, an IL4R-directed toxin, is being studied in a Phase 2b trial in recurrent GBM (rGBM) patients at first or second relapse. MDNA55 is co-infused with Gadolinium-based contrast agent and delivered as a single intratumoral infusion using Convection Enhanced Delivery (CED). Primary endpoint is median Overall Survival (mOS) and secondary endpoint is objective response rate (ORR) assessed by mRANO-based criteria incorporating advanced imaging modalities. Enrollment is complete (n=46). Current safety data show similar profile to previous MDNA55 trials with no systemic toxicities or drug related deaths. Current mOS in subjects treated with low doses of MDNA55 (median 63µg; n=21) is 11.8 months. When stratified by IL4R expression, a biomarker for more aggressive GBM, IL4R+ve subjects (mOS 15.2 months; n=8) show a survival advantage of 7 months compared to IL4R-ve subjects (mOS 8.1 months; n=10). Updated survival and response outcomes including subjects receiving the high dose (median 180µg; n=25) and stratification by IL4R expression will be reported. Review of serial imaging within 90 days following MDNA55 treatment demonstrated tumor shrinkage or stabilization from baseline in 19/42 evaluable subjects (disease control rate of 45%). To account for initial pseudo-progression in some subjects, tumor response was also assessed from nadir: 83% (35/42) showed disease control. Multi-parametric MRI biomarkers including relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) measurements demonstrated distinct imaging phenotypes among different disease states (pseudo-progression vs true-progression, pseudo-response vs true-response) and improved response staging. This trial is advancing neurosurgical methods for CED, potential of IL4R expression as a biomarker to select GBM patients most likely to benefit from MDNA55 treatment, and optimal use of multi-parametric MRI as an adjunct to clinical decision making. The improved survival and disease control seen after only a single infusion of MDNA55, especially in IL4R+ve subjects, may provide promising clinical benefit for rGBM patients.

scholarly journals Multiparametric MRI assessment of response to convection-enhanced intratumoral delivery of MDNA55, an interleukin-4 receptor targeted immunotherapy, for recurrent glioblastoma

2021 ◽  
Vol 12 ◽  
pp. 337
Author(s):  
Suyash Mohan ◽  
Sumei Wang ◽  
Sanjeev Chawla ◽  
Kalil Abdullah ◽  
Arati Desai ◽  
...  
Keyword(s):  
Cerebral Blood Volume ◽  
Therapeutic Potential ◽  
Mean Diffusivity ◽  
Recurrent Glioblastoma ◽  
Perfusion Mri ◽  
Interleukin 4 ◽  
Convection Enhanced Delivery ◽  
Dismal Prognosis ◽  
Interleukin 4 Receptor ◽  
Recurrent Gbm

Background: Glioblastoma (GBM) is the most common malignant brain tumor and carries a dismal prognosis. Attempts to develop biologically targeted therapies are challenging as the blood–brain barrier can limit drugs from reaching their target when administered through conventional (intravenous or oral) routes. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. To circumvent these problems, convection-enhanced delivery (CED) provides direct, targeted, intralesional therapy with a secondary objective to alter the tumor microenvironment from an immunologically “cold” (nonresponsive) to an “inflamed” (immunoresponsive) tumor. Case Description: We report a patient with right occipital recurrent GBM harboring poor prognostic genotypes who was treated with MRI-guided CED of a fusion protein MDNA55 (a targeted toxin directed toward the interleukin-4 receptor). The patient underwent serial anatomical, diffusion, and perfusion MRI scans before initiation of targeted therapy and at 1, 3-month posttherapy. Increased mean diffusivity along with decreased fractional anisotropy and maximum relative cerebral blood volume was noted at follow-up periods relative to baseline. Conclusion: Our findings suggest that diffusion and perfusion MRI techniques may be useful in evaluating early response to CED of MDNA55 in recurrent GBM patients.

CyFi: A phase I study exploring the role of cMET pathway inhibition with ficlatuzumab (Fi) combined with high-dose cytarabine (Cy) in patients with high risk relapsed or refractory acute myeloid leukemia (AML).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7040-7040
Author(s):  
Victoria Wang ◽  
Gabriel N. Mannis ◽  
Rebecca Leah Olin ◽  
Aaron Logan ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Phase I Study ◽  
De Novo ◽  
Elevated Serum ◽  
Fixed Dose ◽  
High Dose ◽  
De Novo Aml ◽  
Poor Outcomes ◽  
Pathway Inhibition

7040 Background: Pts with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum HGF level is an adverse prognostic factor in AML (Verstovsek, et al. 2001; Kim, et al. 2005). Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death (Kentsis, et al. 2012). Methods: We initiated a phase I study to assess the safety and tolerability of Fi combined with Cy in patients with AML who are refractory to 7+3 or have relapsed within 1 year of induction. Fi is given in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks, starting on day 0, and Cy at a fixed dose of 2g/m2 on days 2-7, using a 3x3 design. PBMCs, BM and serum are collected at defined time points to assess HGF levels and activation of the c-Met pathway. Results: Dose escalation is complete and there were no protocol-defined DLTs identified in 9 evaluable pts. All pts treated to date were refractory to induction. Four had de novo AML; 2 had undifferentiated leukemia; 2 prior MDS; 1 prior MPN. Most frequent grade 3/4 TEAEs were febrile neutropenia (56%), LFT abnormalities (11%), and electrolyte disturbance (11%). There was 1 death (11%) from sepsis and multi-organ failure on day 23, following ANC recovery. Of the 7 evaluable pts, 3 achieved a CR (43%), all in the 2nddose cohort. Two of the 3 CRs are long lasting 11 and 12 months following AlloHCT. All patients had detectable circulating HGF levels at baseline compared to control subjects without AML. HGF levels increased following exposure to Fi by an average of 193%. Baseline HGF levels or change from baseline were not associated with treatment response. Conclusions: Ficlatuzumab can be safely combined with HiDAC in this high-risk AML population and produce durable clinical responses. Circulating HGF levels were detectable at baseline and uniformly increased with treatment suggestive of a feedback response or immune complex stabilization. Dose expansion is ongoing. Clinical trial information: NCT02109627.

Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial

2020 ◽  
Author(s):  
Alejandro Krolewiecki ◽  
Adrián Lifschitz ◽  
Matías Moragas ◽  
Marina Travacio ◽  
Ricardo Valentini ◽  
...  
Keyword(s):  
Multicentre Trial ◽  
Antiviral Effect ◽  
High Dose ◽  
Open Label ◽  
Randomised Controlled

Promising Treatments for Obsessive-Compulsive Disorder: A Call for Additional Research

2019 ◽  
Vol 25 (41) ◽  
pp. 5690-5697 ◽  
Author(s):  
Lorrin M. Koran ◽  
Elias Aboujaoude
Keyword(s):  
Behavioral Therapy ◽  
Preliminary Evidence ◽  
High Dose ◽  
Obsessive Compulsive ◽  
Open Label ◽  
Research Attention ◽  
Acceptance Commitment Therapy ◽  
Compulsive Disorder ◽  
Study Designs ◽  
Virtual Reality Exposure

Many patients with OCD respond partially or not at all to standard medications and cognitive behavioral therapy approaches, making alternate treatments necessary. We review the preliminary evidence that exists in support of the use of stimulants, high-dose caffeine, opiates, memantine, ondansetron, ketamine, and transcranial magnetic stimulation in some patients with OCD. Although limited by small or modest sample sizes, open-label study designs, and brief follow-up periods, studies suggest that each of these strategies can help some patients who have inadequately responded to first-line treatments. The existing data and the unmet needs of OCD patients justify research attention to further test these treatments’ safety and efficacy. Previously untested drugs also deserve attention, especially as recent research has suggested new possible contributors to OCD pathophysiology. Similarly, psychotherapeutic interventions beyond CBT should be investigated, and treatments with preliminary evidence in OCD, including Acceptance Commitment Therapy, Danger Ideation Reduction Therapy, and technology-enabled interventions like computerized CBT and Virtual Reality Exposure Therapy, should be carefully tested.

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