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An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection
Haleh Saber1, Pedro Del Valle1, Tiffany K Ricks1
1US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Hematology and Oncology Products, 10903 New Hampshire Ave, Silver Spring, MD 20903, United States.
Abstract:
We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe.
Insights
Selecting the first-in-human (FIH) dose for oncology bispecific antibodies requires careful consideration. Doses based on 10%-30% pharmacologic activity (PA) are generally acceptable, while other methods may lead to unsafe starting doses.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Bispecific antibodies targeting CD3 are crucial in oncology drug development.
- Selecting the appropriate first-in-human (FIH) dose is critical for patient safety and trial success.
Purpose of the Study:
- To retrospectively evaluate nonclinical study approaches for selecting FIH doses of CD3 bispecific constructs.
- To compare FIH doses derived from nonclinical studies with clinical outcomes like maximum tolerated doses (MTDs).
Main Methods:
- Analysis of nonclinical studies for 17 CD3 bispecific constructs.
- Comparison of calculated FIH doses with MTDs, highest human doses (HHDs), or recommended human dose (RHD).
- Evaluation of different dose-selection methodologies, including receptor occupancy and pharmacologic activity (PA).
Main Results:
- Approaches using receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level were found unacceptable.
- FIH doses corresponding to 10%-30% PA were acceptable.
- A FIH dose of 50% PA was acceptable for most constructs, with exceptions possibly due to unique biological properties.
Conclusions:
- Certain nonclinical methods are not suitable for FIH dose selection of CD3 bispecifics.
- Pharmacologic activity (PA) levels between 10%-30% provide an acceptable range for FIH dose selection.
- Intra-patient dose escalation may improve tolerability, but caution is advised regarding MTD exposure in naive patients.
