Inefficiencies in phase II to phase III transition impeding successful drug development in glioblastoma

Abstract

Background Improving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon. Methods Studies between 2005 and 2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was “optimally matched,” where same drug was used in similar schedule and similar population; “suboptimally matched” if dis-similar schedule and/or treatment setting; or “lacking.” Phase II/III transition data were compared by Pearson Correlation, Fisher’s exact or chi-square testing. Results Of 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T, and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 “optimally matched” dyads showed strong concordance for mPFS (r2 = 0.95, P < .01) and mOS (r2 = 0.84, P < .01), while 7 “suboptimally matched” dyads did not (P > .05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. “Newly diagnosed” P2Ts with mPFS < 14 months and/or mOS< 22 months had subsequent negative P3Ts. “Recurrent” P2Ts with mPFS < 6 months and mOS< 12 months also had negative P3Ts. Conclusion Our findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.

A Multicenter, Dose-Escalation, Open-Label, Phase IIa Clinical Trial to Evaluate the Safety and Efficacy of TTAC-0001 (olinvacimab), a Fully Human Monoclonal Antibody in Patients with Recurrent Glioblastoma

“…The validity of these ndings is limited by the small sample size, but remains consistent with prior literature examining agents in rGBM [3]. Trials in rGBM have been historically characterised by low rates of response to treatment [21].…”

“…However, the majority of patients inevitably relapse with recurrent GBM (rGBM). There are few effective agents for rGBM, and median survival for patients with rGBM remains less than 9 months [3,4].…”

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement

“…Compared with randomized studies, single-arm phase II trials require significantly fewer patients and resources and can be opened and completed fairly rapidly at a single institution. However, it is generally agreed upon that the abundance of single-arm efficacy studies with primary endpoint analysis based on historical controls has generated an inadequate phase II program in glioblastoma (17,18,21,22,25). Issues with single-arm phase II designs for glioblastoma trials include a lack of reliable historical controls for most protocols (ref.…”

“…This disconnect between the urgent unmet need, growing scientific understanding of the disease, and lack of translation into effective novel therapies can be attributed to many causes, some of which are related to the difficult biology and clinical challenges inherent to glioblastoma. However, glioblastoma clinical trial design has also attracted significant recent scrutiny and may represent an important barrier to progress (17)(18)(19)(20)(21)(22)(23)(24)(25). Key problems include a paucity of control arms in phase II trials (18,25), overly stringent clinical eligibility criteria and insufficient patient and provider participation (19,20), inadequate assessment of brain penetration (26,27) and pharmacodynamics (28,29) of new drugs, inefficient clinical trial infrastructure (30), and limited development and implementation of prognostic and predictive biomarkers (31)(32)(33)(34)(35)(36)(37).…”