Phase 0 Radiopharmaceutical-Agent Clinical Development

Abstract

The evaluation of antibody-targeted or peptide-targeted radiopharmaceuticals as monotherapy or in oncological drug combinations requires programmatic collaboration within the National Cancer Institute (NCI) clinical trial enterprise. Phase 0 trials provide a flexible research platform for the study of radiopharmaceutical-drug pharmacokinetics, radiation dosimetry, biomarkers of DNA damage response modulation, and pharmacodynamic benchmarks predictive of therapeutic success. In this article, we discuss a phase 0 clinical development approach for human antibody-targeted or peptide-targeted radiopharmaceutical-agent combinations. We expect that early-phase radiopharmaceutical-agent combination trials will become a more tactical and more prevalent part of radiopharmaceutical clinical development in the near-term future for the NCI Cancer Therapy Evaluation Program.

Keywords: cancer; national cancer institute (NCI); phase 0 clinical trial; radiopharmaceutical; radiotherapy.

Figure 1

Stages of radiopharmaceutical–drug development. (A) Depicted are the steps to assess molecular target effects or cytotoxicity of a novel radiopharmaceutical–agent combination. N is the approximate patient sample size necessary to finish the phase of study. Proof-of-concept in vitro and in vivo experiments provide toxicity and efficacy endpoints, most often in two or more disease of interest models, that justify conventional phase I and II testing. (B) Illustrated are the stages to assess molecular target effects or cytotoxicity of a novel radiopharmaceutical–agent combination utilizing a compressed phase 0 approach. X is the estimated number of subjects required to complete a phase 0 study (~8–10). Proof-of-concept in silico or first-in-human microdosimetry studies (i.e., time-concentration studies) provide data that guide the planning and execution in vitro and in vivo in two or more disease of interest models. What follows is a phase 0 trial (pre-phase II trial) in a small number of subjects that use either single or shortened courses of radiopharmaceutical–agent treatment. This type of “target assessment” trial collects not only safety data but also definitive pharmacokinetic parameters, pharmacodynamic endpoints, and tumor responses in subjects with various cancer types. A phase 0 trial might provide a preliminary evaluation of whether irradiation or target engagement associates with clinical endpoints (i.e., tumor response). Phase 0 data inform statistical designs of “target validation” phase II efficacy trials by reducing patient numbers.

Figure 2

Stages of diagnostic-therapeutic or “theranostic” radiopharmaceutical development. (A) Illustrated are the conventional stages of early-phase development of diagnostic–therapeutic radiopharmaceutical pairs [like ⁶⁸Ga (diagnostic) and ¹⁷⁷Lu (therapeutic) for neuroendocrine cancers]. N is the estimated patient sample size needed to complete each study phase. Proof-of-concept first-in-human microdosimetry studies (i.e., time-concentration studies) characterize the initial relationship between antibody-receptor or peptide-receptor ligands using a diagnostic radionuclide (⁶⁸Ga, in this example). Then, phase I patients enrolled with tumors shown to have diagnostic ligand positivity (⁶⁸Ga retention on nuclear medicine imaging) are given therapeutic doses (¹⁷⁷Lu, in this example) with or without oncologic drugs to evaluate the safety of treatment. Efficacy phase II trials are conducted to study clinical endpoints (i.e., tumor response, duration of response, and progression-free or overall survivals). If warranted, definitive phase III trials are done in late-phase development to compare the new treatment to standard treatment. (B) Depicted are the stages of diagnostic–therapeutic radiopharmaceutical pair development engaging a timeline-compressed phase 0 approach. N is the number of patients needed to complete the trial phase. X is the number of phase 0 subjects required for safety, pharmacokinetic, and pharmacodynamic endpoints (~8–10). The phase 0 trial might collect data on (a) a diagnostic radionuclide (i.e., an uptake radiotracer, ⁶⁸Ga-dotatate) to demonstrate target positivity integral for trial eligibility before giving a therapeutic dose of an investigational radiopharmaceutical, (b) a conventional response indicator [like ¹⁸F-FDG positron emission tomography (PET)] as an integral clinical response endpoint assessment, and (c) a dosimetry radionuclide (i.e., localization radiotracer) to gauge actual irradiation dose in targeted tumors. Efficacy phase II trials are then conducted with a focused diagnostic–therapeutic radiopharmaceutical response with dosimetry substudies. If promising, a definitive phase III trial follows to contrast clinical endpoints after new or standard treatments.

Figure 3

Phase 0 trial pharmacodynamic efficacy endpoints. Illustrated here are the two vital study design considerations for a phase 0 trial with pharmacodynamic efficacy endpoints. Baseline and posttherapy biomarker assessments are obtained for pharmacodynamic response. Response is defined by two parameters—a pharmacodynamic response and a prespecified cohort response. (A) A pharmacodynamic response is scored positive when a biomarker signal [like γH2AX foci immunofluorescence area (green dots)] passes a prespecified threshold for biomarker effect. (B) A prespecified cohort response is scored positive when the number of subjects showing a positive pharmacodynamic response passes a prespecified threshold for “positive” proportion. This two-step process defines what establishes a favorable observed pharmacodynamic response rate in the phase 0 trial—in other words, how many subjects must demonstrate a pharmacodynamic response for the phase 0 trial to be declared biologically effective. This is parallel to determining a threshold for observed response rate in a phase II trial in order that the radiopharmaceutical–agent combination be considered sufficiently favorable for further testing in trials.

Figure 4

Multiple dose radiopharmaceutical–agent combination phase 0–II trial with imaging endpoints. Schemed here are the elements for one example of a phase 0 dose or schedule-finding trial transitioning to a phase II efficacy trial with imaging biomarkers. Figure 2 discusses the phase 0 trial approach. In phase II, baseline diagnostic imaging (like an uptake radiotracer, ⁶⁸Ga-dotatate) and conventional response indicator [like ¹⁸F-FDG positron emission tomography (PET)] is acquired for reference. A target-modifying agent (or drug) is given, and then repeat diagnostic uptake radiotracer imaging is acquired to triage patients with “positive” tumors forward to therapeutic radiopharmaceutical treatment. On the day of radiopharmaceutical delivery, a dosimetry substudy [like a single photon emitted computed tomography (SPECT) scan for ¹⁷⁷Lu-dotatate] is done for the purpose of calculating actual irradiation dose in targeted tumors. What follows are multiple administrations of radiopharmaceutical–agent combination treatments in prespecified doses and schedules. A defined dose-limiting toxicity observation window (for up to two cycles to capture “late” adverse events) is used for safety endpoints. The conventional response indicator performed at baseline is repeated (like after two cycles) for response assessment. Compelling results from a phase 0–II trial approach might lead to definitive phase III trials. It is important to note that links or discussion of this radiopharmaceutical–agent phase 0–II trial design does not constitute endorsement nor commit the US Federal government to this approach.