In recent years, there has been unprecedented acceleration in the development of novel therapies in hematology, such as ex vivo hematopoietic stem cell gene therapy for severe combined immunodeficiency (SCID), AAV-mediated gene transfer for hemophilia B, and p-selectin monoclonal antibody for the prevention of pain crises in sickle cell disease.
The August 2017 FDA approval of tisagenlecleucel (Kymriah™) was an historic milestone, ushering in a new approach to the treatment of hematologic malignancy with adoptive autologous chimeric T cells. At this frontier of medical innovation, groundbreaking therapies are creating an inflection point in our ability to treat — and even cure — intractable illnesses. They also herald an era of novel therapies that can be used to supplant or supplement the armamentarium of prior standard of care treatments.
With emerging therapies, many of which may be delivered as one-time treatments, dose-finding and safety studies are more critical than ever. Dose-finding for novel therapies often requires titration to a biologically effective dose, rather than a maximum tolerated dose where toxicity is the limiting factor. These novel therapies often have limited toxicity, as compared to older, now standard, treatments. When present, treatment emergent adverse events may not be dose dependent and, as in the case of CAR-T, may actually indicate efficacy. Therefore, a dose escalation method with toxicity-based endpoints is less relevant for determining a recommended biologically effective dose, and alternative parameters such as pharmacodynamic or efficacy endpoints may be more appropriate.
Sponsors of emerging hematologic therapies — including gene transfer and gene editing, adoptive cellular and antibody-drug conjugates — face a unique set of challenges in conducting early-phase, dose-finding studies. Key considerations for developing early phase trials that can more accurately define the recommended dose and identify adverse events for emerging therapies include:
- Using dose-finding trial designs with the goal of establishing a biologically effective dose, especially when toxicity is not expected to be limiting.
- Using pharmacokinetic or pharmacodynamic endpoints from preclinical models to predict a range of biologically active doses and inform dosing schedules.
- Utilizing adaptive trial designs to enable improved, early insight into treatment effect and allow for increased flexibility in study outcomes.
- Identifying and selecting investigators and sites that have experience in recognizing, characterizing and monitoring adverse events outside of standard toxicities defined by NCI CTCAE criteria.
- Managing safety review activities rigorously to facilitate appropriate, expeditious dose cohort escalation decision-making activities.
- Managing the collection and sharing of data in real time across sites.
For pediatric and rare diseases, the inherent challenges of designing early phase studies for emerging therapies are compounded by special considerations for the patient population under investigation.
Dose-finding and safety studies for novel therapeutic platforms being employed for hematology require sophisticated execution. Working with a CRO that has deep, multifaceted experience in novel therapies for hematology (cellular, gene transfer, immune-based), pharmacovigilance, pediatric diseases, rare diseases and global, multicenter trials can help biotech and pharma sponsors navigate these studies more efficiently and successfully.