Toward better early-phase brain tumor clinical trials: A reappraisal of current methods and proposals for future strategies

Abstract

Although no optimal treatment is currently available for malignant brain tumors, as the molecular mechanisms underlying brain tumor development have been delineated, new chemotherapeutic agents that act directly on speci c molecular targets have become available. De ning a speci c molecular target raises the possibility that the molecular effects of a given agent can be analyzed in patients in a clinical trial. Speci cally, whereas standard phase I and II clinical trials classically determine the safety and ef cacy of agents by using indirect global end points, these new biological agents afford the opportunity to incorporate molecular end points into phase I and II clinical trials to determine whether the agent under investigation is actually doing what it was intended to do. This work presents avenues for improving current brain tumor clinical trial designs based on the molecular speci city of new agents and the unique features of brain tumors. Speci cally, the authors recommend brain-applicable phase I and II clinical trial strategies that take advantage of the targeted nature of new agents to maximize information about their ef cacy, toxicity, and molecular effects.

The tumor microenvironment expression of p‐STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models

“…Determination of CNS intratumoral levels of CTX could be elucidated in dogs diagnosed with CNS melanoma or alternatively, within the context of a clinical trial involving a small cohort of patients before initiation of a larger Phase II study, by preoperative administration of CTX, surgical resection of the CNS melanoma metastasis and the direct determination of the intratumoral concentrations of CTX. 49 In conclusion, we have shown a significant additive antitumor effect of WP1066 with cytotoxic dosing of CTX in an established murine intracerebral melanoma model, which suggests that further clinical testing of the combination of a STAT-3 inhibitor with CTX appears warranted.…”

Mechanisms of action of rapamycin in gliomas

“…Reliance on these indirect end points leaves unanswered important questions such as whether the drug actually reaches the tumor and whether it alters the biology of the tumor. Consequently, investigators have proposed revising the standard clinical design of brain tumor trials to also include assessments of molecular targets to optimize dose and to determine effi cacy (Lang et al, 2002). For these trials to be successful, however, preclinical studies must be aimed at defining the appropriate molecular end points and developing clinically applicable assays to assess these end points (Lang et al, 2002).…”

“…Consequently, investigators have proposed revising the standard clinical design of brain tumor trials to also include assessments of molecular targets to optimize dose and to determine effi cacy (Lang et al, 2002). For these trials to be successful, however, preclinical studies must be aimed at defining the appropriate molecular end points and developing clinically applicable assays to assess these end points (Lang et al, 2002). A molecular approach makes more effi cient use of animal studies given the frequent observation that effi cacy in animals only rarely correlates with effi cacy in humans.…”

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

“…Furthermore, free (unbound) levels of the drug should be sufficient to have a potential pharmacodynamic effect . The use of treat‐biopsy and biopsy‐treat‐biopsy paradigms provides invaluable information regarding drug delivery, pharmacodynamics, and potential mechanisms of resistance . The combination of an optimized clinical trial design and promising new classes of agents such as dual PI3K/mTOR inhibitors that should block feedback activation of Akt offers hope of improved outcomes.…”