Advances in our understanding of the genetic drivers of cancer and the immune system’s complex response to cancer have led to significant breakthroughs in the treatment of hematological malignancies. While gene therapy technologies are addressing unmet needs in hemato-oncology, the design and execution of clinical trials of these therapies can be challenging.
Obstacles in researching cancer immunotherapy range from variability in patient response and inability to predict treatment efficacy to appropriate endpoint selection, safety considerations, and recruitment. Planning and operationalizing clinical studies of immuno-gene therapeutics to achieve conclusive data outcomes requires sponsors to select an appropriate regulatory pathway and understand the nuances of endpoint selection, adverse event management, site selection, and patient engagement.
Current Trends in Gene Therapy Technologies for Hemato-oncology
Among the wide array of gene therapy technologies, therapeutic cancer vaccines and adoptive cell transfer therapies are the most studied to date. Therapeutic cancer vaccines aim to help the body’s own T-cells produce more anti-cancer T-cells and may be cellular-based, protein-based, or vectorbased. Adoptive cell transfer therapies involve taking T-cells from a patient, modifying and expanding them ex vivo, and then infusing them back into the patients. These therapies may be tumor infiltrating lymphocytes (TILs), T-cell receptors (TCRs), or chimeric antigen receptor (CAR)-T cells.
In August 2017, the U.S. Food and Drug Administration approved the first-ever chimeric antigen receptor (CAR)-T therapy, tisagenlecleucel (marketed as Kymriah™).1 This landmark approval was followed by the approval of axicabtagene ciloleucel (marketed as Yescarta™) in October 2017.2 The hefty price tag of these therapies reflects not only the complex drug development pathway for immuno-gene therapeutics, but also the complexity and coordination involved in manufacturing and administering them. Thus, for many immuno-oncology (IO) agents, the product technology may influence or even define the clinical trial strategy.
Defining a Target Indication
The Cancer Research Institute (CRI) recently published an independent analysis of the global IO landscape. CRI’s database actively tracks over 2000 IO agents, of which 940 are currently in clinical development.3 In this competitive clinical trial landscape, sponsors need to strategically define their target indication(s) to improve access to patients and increase the likelihood of success.
Understanding the Regulatory Environment
Successful study planning for therapeutic cancer vaccines and adoptive cell transfer products begins with a detailed understanding of the regulatory environment. Guidance from the European Medicines Agency (EMA) on anti-cancer medicinal products provides the following guidelines on immuno-modulating products, including vaccines:5
- Non-clinical in vitro and in vivo proof-of-concept studies are required to justify the planned starting dose and schedule in phase I studies.
- Rationale for the starting dose may be supported using the “Minimal Anticipated Biological Effect Level” (MABEL) approach, or by non-clinical and clinical data from related compounds.
- Information on the differential expression of the target antigen in human tumor and healthy tissues should be provided.
- In cases where no relevant and predictive animal model is available, in vitro studies with human cells might be suitable.
- The aim of early clinical trials is to determine safety, as well as the dose and schedule that induced a desired immune response.
- Dose-finding studies are generally needed to establish the recommended phase II dose.
- Monitoring the immune response (i.e., the induction of antigen-specific T cells or the presence of a humoral response) is of interest for determining appropriate dose and schedule.
More recently, the EMA published a concept paper on the revision of the guideline on quality, non-clinical, and clinical aspects of medicinal products containing genetically modified cells.6 The FDA also published guidance on clinical considerations for therapeutic cancer vaccines.7 This guidance provides guidelines on early-phase and late-phase studies, as well as general considerations regarding study conduct.
Accelerated Regulatory Pathways
There are several accelerated regulatory pathways for immune oncology agents, including orphan designation or regenerative medicine advance therapy (RMAT) designation. A drug is eligible for RMAT designation if:8
- The drug is a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations;
- The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or conditions; and
- Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.
Receiving RMAT designation is a prerequisite for certain gene therapy drugs to take advantage of accelerated pathway options such as Fast Track, Accelerated Approval, Breakthrough Designation, and Priority Review.
In the EU, accelerated regulatory pathways for innovative products include the following non-mutually exclusive options:
- Accelerated Assessment. This pathway offers a reduced timeframe for review for major public health interest and therapeutic innovation.9
- Conditional Marketing Authorization. This allows marketing authorization before complete data are available but requires annual review. To be eligible, the product must treat, prevent, or diagnose seriously debilitating or life-threatening diseases, be intended for use in emergency situations, or be designated as an orphan medicine.10
- Compassionate Use. This pathway allows the use of an unauthorized medicine for patients with unmet medical needs. The Committee for Medicinal Products for Human Use (CHMP) issues an opinion on criteria and conditions, which national patient access programs can consider when making such medicines available.11
- PRIME. This allows for early identification of accelerated assessment and provides additional scientific advice and a dedicated EMA contact.12
Selecting Appropriate Endpoints
The mechanism of action of immunotherapy differs significantly from chemotherapy. As such, endpoints that are suitable for chemotherapeutic agents may not be appropriate for immunotherapeutic agents. Moreover, the toxicities associated with immunotherapy may differ from or augment those associated with chemotherapy.
Currently, the FDA is debating appropriate clinical trial endpoints for immuno oncology studies. Revision of previously accepted response criteria may be needed, as exemplified by the proposed refinement of the Lugano Classification response criteria for lymphoma in the setting of immunomodulatory therapy. The adapted criteria, known as the Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC), introduce the term “indeterminate response” to describe lesions prior to confirmation as pseudo-progression or progressive disease by either biopsy or subsequent imaging.13
As an increasing number of studies involve immuno oncology agents as part of a combination therapy, either with another immunotherapeutic agents or with a targeted or cytotoxic therapy, endpoint selection will become even more challenging.
Managing Adverse Events
The unique safety considerations associated with immuno-oncology agents may impact both trial design and management.
CAR-T therapies have been associated with serious toxicity, including cytokine release syndrome (CRS), CAR-T cell-related encephalopathy syndrome (CRES), and hemophagocytic lymphohistiocytosis (HLH). Combination studies with other IO therapies could potentially accentuate toxicity in terms of both severity and range of AEs. Consequently, regular safety review meetings and Data Safety & Monitoring (DSM) are required, and adjudication of dose-limiting toxicities (DLTs) may be considered.
As part of study planning, the following safety considerations should be defined in the protocol:
- Prophylactic measures
- Management and dose adjustments of other medication
- Permissible concomitant medications and supportive care
- Any immediately reportable AEs
- What does not need to be reported, e.g., progression of disease
For CAR-T therapies, it is also important to consider the following variables:
- Concomitant medications
- Disease being studied, prior lines of therapy, and disease burden
- CAR design and production and amplification of the CAR-T cell
- Patient pre-conditioning and administered doses
Choosing the Right Sites
In today’s competitive clinical trial landscape, it is important to adopt a data driven approach to selecting the right sites and the right countries. The Foundation for the Accreditation of Cellular Therapy (FACT) at the University of Nebraska Medical Center offers accreditation to sites that excel in patient care and laboratory practices, which may help sponsors and contract research organizations (CROs) in selecting potential sites for trials of IO agents.
For global studies, it is important to remember that the EU comprises a number of countries, which may involve additional procedures outside of standard regulatory and ethical review. Certain EU member states may also require notification to other bodies when a clinical trial of an IO agent is being conducted. Sponsors should also invest time in understanding the difference between the contained use (Directive 2009/31/EC) and deliberate release (Directive 2001/18/EC) risk classifications for genetically modified organisms (GMOs), and how each EU member state regards clinical trials with immuno-gene therapeutics. Additional rationale and scientific documents, such as an environment risk assessment or summary notification information format (SNIF), may be required.
Recruiting and Engaging Patients
Sponsors of early-phase trials can expect strong competition for both study site resources and patients. Consequently, recruitment modelling should include data from multiple sources, including:
- Epidemiology data
- Competitive landscape
- Country experience
- Distribution of experienced investigators
- Electronic health records showing lines of therapy
Patient engagement strategies should span the entire clinical development lifecycle, from preclinical planning to post-submission. Getting patient advocacy groups involved early in the planning process may be invaluable in building strong relationships with patients and their families.
Getting Started
Immuno-gene therapeutics are transforming the treatment landscape in hematological malignances. While designing and operationalizing clinical studies of these therapies can be complex, proactive planning that puts patients first can help streamline the path to conclusive data outcomes and successful commercialization.
References
- U.S. Food and Drug Administration. FDA approval brings first gene therapy to the United States. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm. Accessed February 23, 2018.
- U.S. Food and Drug Administration. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm. Accessed February 23, 2018.
- Cancer Research Institute. Cancer Research Institute Announces Publication of Comprehensive Immuno-Oncology Landscape Analysis in Annals of Oncology. Available at https://www.cancerresearch.org/news/2017/cri-immuno-oncology-landscape-analysispublication. Accessed February 23, 2018.
- Tang J, et al. Comprehensive analysis of the clinical immuno-oncology landscape. Ann Oncol 2018;29(1):84-91.
- European Medicines Agency. Guideline on the evaluation of anticancer medicinal products in man. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/11/WC500238764.pdf
- European Medicines Agency. Concept paper on the revision of the Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500231995.pdf.
- U.S. Food and Drug Administration. Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines. Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM278673.pdfg
- U.S. Food and Drug Administration. Regenerative Medicine Advanced Therapy Designation. Available at https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm537670.htm.
- European Medicines Agency. Accelerated assessment. Available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000955.jsp&mid=WC0b01ac05809f843a.
- European Medicines Agency. Conditional marketing authorization. Available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000925.jsp.
- European Medicines Agency. Compassionate use. Available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000293.jsp&mid=WC0b01ac05809f843c.
- European Medicines Agency. PRIME: priority medicines. Available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000660.jsp&mid=WC0b01ac05809f8439.
- Cheson BD, et al. Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. Blood 2016;128(21):2489-2496.
- Schuster SJ, et al. American Society of Hematology (ASH) Annual Meeting 2017: Abstract 577.