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.

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

Neuro-Oncology ◽

10.1093/neuonc/noab196.220 ◽

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.

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Recurrent glioblastoma multiforme: a review of natural history and management options

Neurosurgical FOCUS ◽

10.3171/foc.2006.20.4.2 ◽

2006 ◽

Vol 20 (4) ◽

pp. E3 ◽

Cited By ~ 111

Author(s):

Lewis C. Hou ◽

Anand Veeravagu ◽

Andrew R. Hsu ◽

Victor C. K. Tse

Keyword(s):

Glioblastoma Multiforme ◽

Natural History ◽

Research Effort ◽

Treatment Options ◽

Recurrent Glioblastoma ◽

Recurrent Glioblastoma Multiforme ◽

Management Options ◽

Fatal Disease ◽

The Past ◽

Recurrent Gbm

✓ Glioblastoma multiforme (GBM) is one of the most aggressive primary brain tumors, with a grim prognosis despite maximal treatment. Advancements in the past decades have not significantly increased the overall survival of patients with this disease. The recurrence of GBM is inevitable, its management often unclear and case dependent. In this report, the authors summarize the current literature regarding the natural history, surveillance algorithms, and treatment options of recurrent GBM. Furthermore, they provide brief discussions regarding current novel efforts in basic and clinical research. They conclude that although recurrent GBM remains a fatal disease, the literature suggests that a subset of patients may benefit from maximal treatment efforts. Nevertheless, further research effort in all aspects of GBM diagnosis and treatment remains essential to improve the overall prognosis of this disease.

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Propensity score analysis methods with balancing constraints: A Monte Carlo study

Statistical Methods in Medical Research ◽

10.1177/0962280220983512 ◽

2021 ◽

pp. 096228022098351

Author(s):

Yan Li ◽

Liang Li

Keyword(s):

Monte Carlo ◽

Propensity Score ◽

Propensity Scores ◽

Probability Weighting ◽

Inverse Probability ◽

Propensity Score Model ◽

Propensity Score Weighting ◽

Estimation Performance ◽

Score Model ◽

Weighting Methods

The inverse probability weighting is an important propensity score weighting method to estimate the average treatment effect. Recent literature shows that it can be easily combined with covariate balancing constraints to reduce the detrimental effects of excessively large weights and improve balance. Other methods are available to derive weights that balance covariate distributions between the treatment groups without the involvement of propensity scores. We conducted comprehensive Monte Carlo experiments to study whether the use of covariate balancing constraints circumvent the need for correct propensity score model specification, and whether the use of a propensity score model further improves the estimation performance among methods that use similar covariate balancing constraints. We compared simple inverse probability weighting, two propensity score weighting methods with balancing constraints (covariate balancing propensity score, covariate balancing scoring rule), and two weighting methods with balancing constraints but without using the propensity scores (entropy balancing and kernel balancing). We observed that correct specification of the propensity score model remains important even when the constraints effectively balance the covariates. We also observed evidence suggesting that, with similar covariate balance constraints, the use of a propensity score model improves the estimation performance when the dimension of covariates is large. These findings suggest that it is important to develop flexible data-driven propensity score models that satisfy covariate balancing conditions.

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Combined Salvage Therapies for Recurrent Glioblastoma Multiforme: Treatment Options in Multifocal and Multicentric Patterns of Recurrence

Journal of Cancer Prevention & Current Research ◽

10.15406/jcpcr.2017.07.00222 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 1

Author(s):

Eleftherios Archavlis

Keyword(s):

Glioblastoma Multiforme ◽

Treatment Options ◽

Recurrent Glioblastoma ◽

Recurrent Glioblastoma Multiforme ◽

Patterns Of Recurrence

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Safety and efficacy of permanent iodine-125 seed implants and carmustine wafers in patients with recurrent glioblastoma multiforme

Journal of Neurosurgery ◽

10.3171/jns/2008/108/2/0236 ◽

2008 ◽

Vol 108 (2) ◽

pp. 236-242 ◽

Cited By ~ 35

Author(s):

Borimir J. Darakchiev ◽

Robert E. Albright ◽

John C. Breneman ◽

Ronald E. Warnick

Keyword(s):

Glioblastoma Multiforme ◽

Treatment Options ◽

Tumor Resection ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Karnofsky Performance Scale ◽

Recurrent Glioblastoma Multiforme ◽

Brain Necrosis ◽

Bcnu Wafers ◽

Recurrent Gbm

Object Effective treatment options are limited for patients with recurrent glioblastoma multiforme (GBM), and survival is usually <1 year. Novel treatment approaches are needed. Localized adjunct treatment with carmustine (BCNU) wafers or permanent, low-activity 125I seed implants has been shown to be effective for GBM. This study assessed the efficacy and safety of these therapies in combination following tumor resection. Methods Thirty-four patients with recurrent GBM were treated with maximal tumor resection followed by implantation of BCNU wafers and permanent 125I seeds into the tumor cavity. Patients were followed up with clinical evaluations and magnetic resonance imaging studies once every 3 months. Survival and progression-free survival (PFS) were evaluated. Results During follow-up, local disease progression was observed in 27 patients, and 23 of them died. The median survival period was 69 weeks, and the median PFS was 47 weeks. The 12-month survival and PFS rates were 66 and 32%, respectively. Baseline factors associated with prolonged survival included Karnofsky Performance Scale score ≥ 70, 125I seed activity ≥ 0.8 mCi/cm3 of tumor cavity, and age < 60 years. Brain necrosis developed in 8 patients (24%) and was successfully treated with surgery or hyperbaric oxygen therapy. Conclusions The use of adjunct therapy combining BCNU wafers and permanent 125I seeds resulted in survival that compares favorably with data from similar studies performed in patients with recurrent GBM. The incidence of brain necrosis appeared to be higher than that expected with either treatment alone, although the necrosis was manageable and did not affect survival. This novel approach warrants further investigation in recurrent and newly diagnosed GBM.

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Reirradiation and chemotherapy with ifosfamide, carboplatin and etoposide (ICE) for recurrent multiforme glioblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.12508 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 12508-12508

Author(s):

A. Rodica Maricela ◽

L. N. Minea ◽

L. Oprea ◽

T. Georgescu ◽

I. Isacu ◽

...

Keyword(s):

Treatment Options ◽

Haematological Toxicity ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Recurrent Glioblastoma Multiforme ◽

Free Survival ◽

Concomitant Radiochemotherapy ◽

Tumor Bed ◽

One Year ◽

Standard Treatment Regimen

12508 Background: Despite different treatment options no standard treatment regimen is yet available for patient with recurrent glioblastoma, and the prognosis remain poor. In our study our aim was to assess the efficacy of a schedule consisted in Ifosfamide plus Carboplatine plus Etoposide in recurrent multiform glioblastoma patients. Methods: Between January 2002 - December 2006 32 patients have been treated for recurrent glioblastoma multiforme. They were 18 male and 14 female, with median age 44.6 years old (range 22–65 years old). The ECOG was 0–1-2 , 12/14/6 patients respectively. 15 of them received chronic corticotherapy. All patients were previously irradiated and they have inoperable recurrences. After the confirmation of recurrence 30 of them could be reirradiated with 30 Gy using conformal beam radiotherapy on the tumor bed. Three weeks after completion of radiotherapy they receive six cycles of chemotherapy consisted in Ifosfamide 1000 mg/sqm day 1–3 + Carboplatin 75 mg/sqm day 1–3 + Etoposide 75 mg/sqm day 1–3 every 4 weeks, according to hematological tolerance. Results: Reirradiation associated with ICE chemotherapy resulted in one complete remission, three partial remission, and 8 stable disease. All responders were 37.5%. 26 patients survived at least six month and 22 of them received all six cycles. One year survival rate was 21.8%. Progression-free survival at six month was 31.25%. The regimen was well tolerated with mild toxicities. Haematological toxicity gr.I-II 8 pts, gr.III-IV 3 pt; nonhaematological toxicity: fatigability gr.I-II 12 pts., gr.III-IV 2 pt, gr.III-IV 1 pt, nausea gr.I-II 9 pts, gr.III-IV 4 pt, renal toxicity grade I-II 3 patients, Neurological toxicity grade I-II 5 patients. Conclusions: The treatment scheme has been well tolerated. Results are similar with PCV regimen, even slightly better. This regimen should be reconsider for concomitant radiochemotherapy. No significant financial relationships to disclose.

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Validating Four Standard Scales in Spiritually Practicing and Nonpracticing Samples Using Propensity Score Matching

European Journal of Psychological Assessment ◽

10.1027/1015-5759.24.3.165 ◽

2008 ◽

Vol 24 (3) ◽

pp. 165-173 ◽

Cited By ~ 8

Author(s):

Niko Kohls ◽

Harald Walach

Keyword(s):

Propensity Score ◽

Propensity Score Matching ◽

Repeated Measures ◽

Propensity Scores ◽

Total Sample ◽

Experimental Manipulation ◽

Brief Symptom Inventory ◽

Time Interaction ◽

Social Support Scale ◽

Lower Test

Validation studies of standard scales in the particular sample that one is studying are essential for accurate conclusions. We investigated the differences in answering patterns of the Brief-Symptom-Inventory (BSI), Transpersonal Trust Scale (TPV), Sense of Coherence Questionnaire (SOC), and a Social Support Scale (F-SoZu) for a matched sample of spiritually practicing (SP) and nonpracticing (NSP) individuals at two measurement points (t1, t2). Applying a sample matching procedure based on propensity scores, we selected two sociodemographically balanced subsamples of N = 120 out of a total sample of N = 431. Employing repeated measures ANOVAs, we found an intersample difference in means only for TPV and an intrasample difference for F-SoZu. Additionally, a group × time interaction effect was found for TPV. While Cronbach’s α was acceptable and comparable for both samples, a significantly lower test-rest-reliability for the BSI was found in the SP sample (rSP = .62; rNSP = .78). Thus, when researching the effects of spiritual practice, one should not only look at differences in means but also consider time stability. We recommend propensity score matching as an alternative for randomization in variables that defy experimental manipulation such as spirituality.

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Differentiation of Recurrent Glioblastoma Multiforme from Radiation Necrosis after External Beam Radiation Therapy with Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(10)79224-3 ◽

2010 ◽

Vol 2010 ◽

pp. 159-160

Author(s):

A.M. McKinney

Keyword(s):

Radiation Necrosis ◽

External Beam Radiation Therapy ◽

Recurrent Glioblastoma ◽

External Beam Radiation ◽

Dynamic Susceptibility ◽

Recurrent Glioblastoma Multiforme ◽

Beam Radiation ◽

Contrast Enhanced ◽

Perfusion Mr ◽

Perfusion Mr Imaging

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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