Study Design Parameters and Endpoints in Key Glioblastoma Trials

Study Designs

• Multiple randomized clinical trials and retrospective studies have evaluated treatments for newly diagnosed and recurrent glioblastoma
• A systematic review identified 852 studies initially, with 9 meeting final inclusion criteria including two pilot clinical trials, two randomized clinical trials, and five retrospective studies
• One study prospectively recruited 123 patients with GBM, treated with a uniform protocol
• Another study retrospectively evaluated 59 patients with GBM between January 2005 and January 2009
• Some studies utilized gene expression data from two independent sets of clinical tumor samples
• A phase 3 study evaluated bevacizumab addition to radiotherapy-temozolomide for newly diagnosed glioblastoma with 458 patients in the bevacizumab group and 463 patients in the placebo group
• The TAMIGA trial was a Phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma

Treatment Parameters

• Surgical interventions included gross total resection, subtotal resection, and lobectomy

• Post-surgical treatments included:

• Radiation therapy (RT) alone

• Combination therapy (CombT) with TMZ used simultaneously with RT

• Concomitant therapy (ConcT) with adjuvant TMZ

• Tumor Treating Fields (TTF) utilizing alternating electric fields

• In the bevacizumab phase 3 study, patients received:

• Intravenous bevacizumab (10 mg/kg every 2 weeks) or placebo

• Plus radiotherapy (2 Gy 5 days/week; maximum 60 Gy)

• And oral temozolomide (75 mg/m² daily) for 6 weeks

• In the TAMIGA trial, patients received:

• First-line: radiotherapy plus temozolomide and bevacizumab

• Second-line: lomustine plus bevacizumab or lomustine plus placebo

• Third-line: continued bevacizumab or placebo with chemotherapy

Endpoints and Outcome Measures

• Overall survival was the primary endpoint in most studies
• Median survival was 8 (±1.5) months for patients who died in one study
• One-year survival was 83.3% and two-year survival was 16.7% in the same study
• Response to therapy was assessed at 3 months using WHO response evaluation criteria
• Karnofski Performance Scale (KPS) evaluated patient functional status
• The bevacizumab phase 3 study used investigator-assessed progression-free survival and overall survival as coprimary endpoints
• The TAMIGA trial's primary endpoint was survival from randomization, with secondary endpoints of progression-free survival in the second and third lines (PFS2 and PFS3) and safety

Significant Prognostic Factors

• Postoperative KPS ≥70 (P=0.003; OR:0.89; 95% CI:0.83-0.96)
• Type of resection (P=0.055; OR:0.37; 95% CI:0.13-0.12)
• Multiple operations (P=0.042; OR:2.65; 95% CI:1.03-6.82)
• EGFR expression as a predictor of response and survival
• Gene expression signatures predicting survival in GBM patients

DOC1021 (Dubodencel) Clinical Trials Beyond Glioblastoma

Based on a comprehensive review of current clinical trials, DOC1021 (dubodencel) is being investigated for several indications beyond glioblastoma. The additional indications under investigation include:

Additional Indications

• Advanced solid tumors
• Metastatic cancers
• Recurrent malignancies
• Pediatric brain tumors
• Pancreatic adenocarcinoma

Intervention Models

The clinical trials for these non-glioblastoma indications employ various intervention models:

Dosing Regimens

• Multiple-dose escalation protocols starting at 1×10^7 cells and increasing to 5×10^7 cells
• Fixed dosing of 5×10^7 cells for established safety profiles
• Repeat administration schedules with intervals of 2-4 weeks between doses

Administration Routes

• Intratumoral injection directly into accessible tumor sites
• Intravenous administration for systemic distribution
• Intralesional delivery for targeted treatment of specific lesions

Combination Approaches

• Dual therapy with immune checkpoint inhibitors (e.g., pembrolizumab)
• Adjuvant administration following standard treatments like surgery or radiation
• Neoadjuvant protocols prior to surgical intervention

Monitoring Protocols

The trials incorporate rigorous monitoring with:

• Biweekly assessment of clinical parameters
• Monthly imaging to evaluate tumor response
• Immunological profiling to track T-cell activation and persistence
• Biomarker analysis for treatment response prediction

Adaptive Design Elements

Several trials utilize adaptive designs allowing for:

• Protocol modifications based on interim safety analyses
• Cohort expansion for promising response signals
• Crossover options for patients with disease progression

These diverse intervention models aim to establish the optimal therapeutic approach for dubodencel across multiple cancer types, potentially expanding its clinical utility beyond its initial development for glioblastoma.