Major medical breakthroughs can result from translating basic scientific research into practical patient treatments. But how does that happen? “Translational” research, involving close collaborations between scientists, researchers, clinicians, and patients, bridges that gap between laboratory discoveries and patient care by methodically testing new treatment ideas in real-world settings. This process helps identify safe and effective treatments for diseases, often taking years of rigorous testing.
What is a clinical trial?
Successful translation ultimately depends on testing in human volunteers. Clinical trials provide hard data on the safety and effectiveness of novel medicines, devices, and treatment procedures, as well as the reliability of new diagnostics. The US Food and Drug Administration (FDA) and similar groups around the globe enforce ethical guidelines to protect trial volunteers (“subjects”) and ensure research integrity. These regulatory agencies ensure that drugs and medical procedures meet three criteria:
- Safety – they do not cause undue harm
- Efficacy – they produce desired biological and medical consequences
- Effectiveness – they deliver measurable “real world” benefits such as significantly improved survival.
Clinical trials can offer patients early access to new, cutting-edge therapies. For someone with a life-threatening disease such as an inoperable or metastatic cancer with no established effective treatment, the value of participation in a trial is potentially enormous. Advanced fibrolamellar carcinoma (FLC) exemplifies this situation. However, despite extensive lab testing, it is impossible to predict whether a new drug’s benefits will outweigh its downsides. A new treatment based on promising lab studies could easily turn out to be a dud in human patients, and it might do more harm than good. Because trial subjects volunteer to contribute to knowledge about their disease and experimental therapies despite substantial uncertainty concerning their potential individual benefit versus risks, they are widely recognized as “heroes contributing to the future of medicine.”
What are the phases of clinical trials?
FDA approval of a new investigational cancer drug means that the agency has determined the product is safe and effective for its intended use. This allows a trial sponsor (often a corporation) to market the medicine in the United States. The path to approval has four phases:
- Phase 1: Mainly tests whether a new treatment, like a drug or combination of therapies, is safe. While for many medical conditions Phase 1 preferably is carried out in healthy volunteers, human testing for cancer medicines often occurs from the beginning in people with the disease. Primary goals include determination of the correct dosage and identification of side effects, along with initial indications of efficacy in a small group of patients.
- Phase 2: Focuses on how well the new treatment works, usually at the highest tolerated or most effective predicted dose based on Phase 1 data. A Phase 2 study generally aims to reach a meaningful result, i.e., one not due merely to chance. Typically, a Phase 2 study concentrates on a particular stage and/or type of cancer (e.g., by organ) or cancers meeting precise diagnostic criteria such as involvement of a specific cell type or the presence of a genetic marker. It also collects more information on safety and side effects. In some instances, to accelerate testing Phases 1 and 2 are combined in a Phase 1/2 study.
- Phase 3: Assesses safety and efficacy in a definitive, statistically robust study with clear success criteria. Often compares a new treatment with the current standard treatment, if one exists. The scale may be hundreds to thousands of patients. However, fewer subjects may be needed for a study of a rare cancer, especially if a treatment proves strongly beneficial. The FDA generally decides whether to approve a drug or treatment based on Phase 3 results, sometimes from two or more independent studies.
- Phase 4: Conducted after a treatment has been approved by the FDA. It monitors long-term data to corroborate safety and effectiveness.
In some trials the subjects in Phase 2 and Phase 3 are divided randomly into different groups to enable blinded comparison of different treatment alternatives. Placebo controls (subjects not receiving any active treatment) may be included if there is no proven effective treatment for the condition and when withholding treatment poses negligible risks to participants.
Who approves and monitors clinical trials?
Clinical trials must be approved by several entities to ensure they are safe, ethical, and scientifically sound before they can proceed. These groups include:
- Institutional Review Boards (IRBs) or Ethics Committees: An IRB is an independent committee that reviews and approves the design of clinical trials to ensure that the study meets ethical standards and protects the rights, safety, and well-being of participants. IRBs typically include members with diverse expertise in science, medicine, and ethics, and representatives of the general community from which trial participants are drawn. The IRB reviews informed consent documents, study protocols, potential risks, and benefits, ensuring that the trial is conducted in a way that minimizes harm to participants.
- Regulatory Agencies:
- U.S. Food and Drug Administration (FDA): In the United States, the FDA oversees the approval of clinical trials for new drugs, medical devices, and biologics. Before clinical trials can begin, sponsors must submit an Investigational New Drug (IND) application or Investigational Device Exemption (IDE), depending on the specifics of the trial. The FDA evaluates the safety and scientific basis of the trial before granting approval.
- European Medicines Agency (EMA): In Europe, the EMA plays a similar role, reviewing and approving clinical trials involving new treatments or drugs.
- Other national health regulatory bodies: Different countries have their own regulatory bodies that evaluate clinical trials within their jurisdictions (e.g., Health Canada, the Therapeutic Goods Administration in Australia, and the Medicines and Healthcare products Regulatory Agency in the UK).
- Data Safety Monitoring Boards (DSMBs): DSMBs are independent committees that monitor the progress of ongoing clinical trials, ensuring that the trial remains ethically and scientifically valid. They review study data to ensure participant safety, the efficacy of the studied intervention, and the integrity of the accumulated data. If they identify safety concerns or see that a treatment is particularly effective, they can recommend stopping or modifying the trial.
Together, these bodies ensure that clinical trials are designed and conducted in a way that minimizes risks, protects participants, and provides reliable data to evaluate the safety and efficacy of new treatments.
Who pays for clinical trials?
In most cases, clinical trials do not cost participants anything for the study-related treatments or procedures, but there could be some expenses depending on the specifics of the trial and the participant’s insurance situation. Costs associated with the trial (such as treatment, medications, or tests) are generally covered by the sponsor (e.g., pharmaceutical companies, government agencies, or nonprofit organizations). However, there are some exceptions and potential costs that patients should be aware of, including costs for routine medical care that is unrelated to the clinical trial or costs of side effects or complications that are unrelated to the study.
Patients are typically informed about any potential costs and coverage through the informed consent process, where they are provided with details about the trial, including costs. It’s important for participants to ask the study team about what costs will be covered and which, if any, will be their responsibility.
Who can participate in a clinical trial?
Trial protocols must include a clear statement of who is eligible to participate as a subject. The criteria for inclusion or exclusion may include age, sex, the exact diagnosis and stage of disease, overall health status when entering the study, medical history, previous treatments, genetic factors, and current medications. An important element of clinical trials is that the subjects in each phase must voluntarily agree to participate after being informed in writing of the trial’s purpose, procedures, potential risks, and benefits. They may not be coerced to participate, nor induced to do so by an excessive financial or other reward.
For cancers with approved treatment(s), new therapies often are tested in subjects who have failed to respond successfully to the standard mode(s) of therapy, or who have suffered disease progression or relapse after an initial positive response. It is not unusual for the FDA to approve a new anti-cancer therapy for use as a second-line or third-line treatment after previously established options have been exhausted. However for a cancer which lacks an existing approved treatment the goal usually is to obtain approval for a therapy that would potentially become the first-line standard of care. In addition, for such cancers, participation in a clinical trial may be the preferred first treatment option.
A cancer treatment also may be tested and approved for use “in the adjuvant setting.” This refers to therapy given after a primary intervention such as surgery, with the aim of preventing the cancer from returning. Even when an operation or radiation therapy successfully eliminates all tumor tissue that can be detected by CT scans or MRIs, microscopic tumors and tiny clusters or individual cancer cells may remain. These could be near the original site of the main tumor, or dispersed to distant locations in the body where they could grow into metastatic tumors. Adjuvant therapy is intended to eliminate or control such residual cancer cells so that the disease does not return. While many oncology clinical trials focus on the reduction of visible tumor masses, treatments also can be tested and receive FDA approval based on the extension of disease-free survival or overall survival when given as adjuvant therapy.
Selected recent and upcoming FLC clinical trials
Recent advances in translational research on FLC are reflected by an increasing number of clinical trials designed to test new therapeutics. The trials described below are given with their identification numbers and titles from the ClinicalTrials.gov web site maintained by the US National Library of Medicine (NLM) at the National Institutes of Health (NIH).
Peptide Vaccines Targeting “DP”, the FLC Oncogenic Driver
- NCT04248569. DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma
- NCT05937295. FusionVAC22_01: Fusion Transcript-based Peptide Vaccine Combined With Immune Checkpoint Inhibition (FusionVAC22)
As described in “Perspectives on FLC immunotherapy”, FLC cells can be killed by immune T cells which make a T-cell receptor (TCR) specific to the DNAJB1::PRKACA fusion protein that drives the cancer. Research teams at Johns Hopkins University (JHU) in the US (NCT04248569, led by Mark Yarchoan and Marina Baretti) and at University Hospital Tübingen, Baden-Würtemberg, Germany (NCT05937295, led by Juliane Walz) have developed similar experimental “therapeutic vaccines” designed to greatly expand the population of anti-DP killer T-cells in a patient’s body. These two trials are enrolling patients with advanced FLC. In each case the vaccine is a chemically synthesized peptide (a short fragment of a protein chain), 22 or 24 amino acids long, overlapping the junction between the “D” and “P” portions of DP, which occurs at exactly the same point in nearly all FLC patients. In addition to the vaccine, trial subjects also are treated with one or two FDA-approved immune checkpoint inhibitors (ICIs), to inactivate “braking signals” that cancer cells use to shut down the anti-tumor response of a patient’s T cells.
The trial at JHU began enrolling subjects with metastatic FLC in April 2020, and it continues to recruit new participants. Interim results have been reported at several international conferences, and the work is being reviewed for publication in a high impact scientific journal. Roughly three-fourths of subjects developed a strong immune response to the peptide vaccine, as shown by the presence of circulating T cells with receptors that recognized the immunizing DP peptide. Nearly every one of these responders showed some clinical benefit, meaning that at a minimum their tumors stopped expanding over a period of many months. Moreover, in about one-third of this subset, the tumors shrunk dramatically. In some cases, the subjects now have “clean” scans, and several are classified as being in complete remission from their cancer. While the total number of patients enrolled in the study is still relatively small, the results to date are by far the most positive yet seen in a clinical trial focused on FLC.
Interim results from the trial at Tübingen have not yet been reported. However, as detailed in the “Perspectives” article, the group has published a detailed paper on testing of their peptide vaccine in healthy human volunteers and in one subject with advanced FLC. The latter patient, who previously had been experiencing repeated, rapid recurrences of metastatic FLC, remains cancer-free more than four years after receiving the vaccine.
The FCF also has awarded a grant to the Tübingen team to carry out a clinical trial of the peptide vaccine (Fusion-VAC-XS15) as adjuvant therapy. (https://fibrofoundation.org/fcf-funds-clinical-trial-at-university-hospital-tubingen/) Subjects will be FLC patients who have no tumors detectable by radiological scans, either after primary surgery or any other treatment(s). Major goals will be to determine whether the vaccine alone (without ICI immunotherapy) can stimulate the expansion of anti-FLC immune cells, and whether it can extend the disease-free period before recurrence or improve overall survival.
Metabolic Therapy: Glutamine Antagonist
- NCT060270861. DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC)
This clinical trial is open to patients with advanced FLC. It is based on the finding that FLC is a “glutamine addicted” cancer (https://fibrofoundation.org/attacking-the-metabolism-of-flc/). The treatment combines an experimental drug, DRP-104 with durvalumab, an FDA-approved ICI. The goal is to attack FLC in two complementary ways:
- Inhibiting the growth of FLC tumors by inactivating a slew of enzymes the cancer cells need to metabolize glutamine. FLC cells utilize this abundant amino acid both as a fuel to burn for energy and as a building block for many “macromolecules” that cancer cells must manufacture to grow and multiply in the body. The DRP-104 drug should inhibit both processes.
- Changing the tumor microenvironment (TME) of FLC from immune-suppressive to “immune-friendly,” so that anti-FLC immune cells can attack and kill the cancer cells. The hyperactive metabolism of glutamine by FLC cells deprives anti-cancer immune cells that invade the tumor of this amino acid, which they also need to multiply and to carry out their anticancer killing function. Furthermore, breakdown products of glutamine metabolism, including lactic acid and ammonia, are spit out into the TME where they are toxic to immune cells. Preventing the buildup of these toxins helps the immune cells to function properly. In addition, simultaneous treatment with the ICI durvalumab should stop the cancer cells from applying the “brakes” that help them turn off the attack by immune cells.
Enabling Chemotherapy by Helping Cancer Cells Self-Destruct
- NCT06620302. Testing the Addition of an Anti-cancer Drug, DT2216, to the Usual Chemotherapy Treatment for Relapsed or Refractory Solid Tumors and Fibrolamellar Carcinoma
Since FLC was first described as a distinct type of cancer, oncologists have observed that it is broadly resistant to classical chemotherapy. These drugs generally kill dividing cells in ways that directly threaten their genetic integrity: damaging DNA; interfering with DNA replication; mucking up cell division, especially the segregation of matched sets of chromosomes into the two daughter cells. Remarkably, these disparate types of damage all induce cells to self-destruct via a precise program – a kind of cellular hare-kiri ritual called “apoptosis.” It results in the extensive breakdown of the dying cell’s contents and packaging of the debris into neat bundles which are efficiently gobbled up and cleared away by specialized garbage removing cells.
Apoptosis is a tightly controlled progress. A family of proteins named “BCL-2,” after its first known member, regulate the triggering of programmed death. The family includes both anti-apoptotic and pro-apoptotic members which interact closely as “changing partners in the dance towards death” (J. Kale et al., in Cell Death & Differentiation, 2017). Sanford Simon’s group at Rockefeller University reported that one important anti-apoptotic “dancer”, named BCL-xL, is strongly expressed in many FCF tumors and that increases resistance of the cancer cells to chemotherapy. After screening more than 5,000 drugs to find those that could induce programmed death in a set of FLC tumors, the Rockefeller team concluded that the combination of a well-established chemotherapy drug, irinotecan (an inhibitor of a DNA “unwinding” enzyme called topoisomerase I), with an inhibitor of BCL-xL appeared promising. They chose an experimental anti-BCL-xL agent, DT2216, an example of a new class of “protein degrader” drugs, to pair with irinotecan, because it was designed to avoid a limiting side effect common to other inhibitors of the same protein. A Phase 1/2 clinical trial of the irinotecan / DT2216 combination is scheduled to begin enrolling patients in January or February 2025. It will be sponsored by the Children’s Oncology Group (COG), and led by Drs. Michael Ortiz (Memorial Sloan Kettering Cancer Center, New York, NY) and Allison O’Neill (Dana-Farber Cancer Institute, Boston, MA).
Summary
Clinical trials are crucial to advancing patient care in rare diseases like FLC, making sure that important scientific learnings find their way “from the bench to the bedside”. They are essential for developing new treatments, ensuring their safety, improving patient outcomes, which ultimately benefits both individuals and society as a whole.
Patients may choose to participate in a clinical trial for several important reasons:
- Access to new treatments: Clinical trials often provide access to cutting-edge treatments or therapies that are not available to the general public.
- Contributing to medical advancements: By participating in a clinical trial, patients play a crucial role in advancing medical research. Their involvement can benefit future generations by improving disease prevention, treatment, or management.
- Potential for improved outcomes: While there are no guarantees, clinical trials may provide access to more effective treatments for patients with conditions that are difficult to treat or for whom current treatments are ineffective.
- Close monitoring and care: Patients in clinical trials often receive more frequent monitoring and care than those who are not in a trial. This can include regular check-ups, lab tests, and consultations with specialists, helping to detect health issues earlier and ensuring that participants are well cared for throughout the study. Clinical trials are also often conducted at leading medical centers or research institutions, giving participants access to some of the best healthcare providers, researchers, and specialists in their field.
Clinical trials are an essential component of medical progress. However, it’s important for patients to carefully consider the potential risks and benefits, consult with their doctors, and fully understand the details of any clinical trial before participating.