NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers

Abstract

The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry's diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials-acute toxicity and maximum-tolerated dose-are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II "screening" trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation.

Adapting a Drug Screening Platform to Discover Associations of Molecular Targeted Radiosensitizers with Genomic Biomarkers

“…To detect those associations, panels of ~50–100 cell lines will be needed. This represents a very different approach from traditional investigations of IR/drug combinations which have utilized only small numbers of in-vitro cell lines for a given cancer type (3, 17), consistent with the traditional “one size fits all” philosophy of combining IR with drugs in patients.…”

“…The importance of pre-clinical and clinical drug development with IR and its challenges have been highlighted (17–20). Historically, the choice of radiosensitizers has conformed to a “one-size-fits-all” philosophy, but it has become increasingly apparent that radiosensitizing effects may be genotype-dependent, requiring predictive biomarkers for appropriate patient selection (21, 22).…”

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

“…A pathway for the development of radiation modifiers published recently (8, 67) suggests modifications to address the new biology; however time-honored assessments often referred to pejoratively as “classical” remain critical to both drug and radiation clinical trials (66). While animal normal tissue models may provide only limited information, normal tissue injury remains an integral part of preclinical development (67, 68) The need for studies will depend on the size of the treatment field as highly focused radiation fields in some regimens are designed to be at tissue-damaging doses to limited volumes and thereby minimizing clinically significant late effects.…”

“…While animal normal tissue models may provide only limited information, normal tissue injury remains an integral part of preclinical development (67, 68) The need for studies will depend on the size of the treatment field as highly focused radiation fields in some regimens are designed to be at tissue-damaging doses to limited volumes and thereby minimizing clinically significant late effects.…”

Radiosensitizers in pancreatic cancer—Preclinical and clinical exploits with molecularly targeted agents

“…Therefore, there has been evolving interest in identifying agents that selectively target tumor-specific pathways important in RT-induced cell death with the goal of augmenting the effects of RT while minimizing sensitization of normal tissues. Many of the targeted agents currently studied as potential radiosensitizers are cytostatic [3]; unlike conventional cytotoxic chemotherapies, these agents may avoid or reduce normal tissue toxicity by exploiting molecular differences between malignant and nonmalignant cells.…”