Funded clinical trials

Timeframe: 2025 - 2028

Goal: Provide the drug necessary to enable a FLC clinical trial

Grantee: Dialectic Therapeutics, Inc.

Principal Investigators of related clinical study: Dr. Allison O'Neill, Dana-Farber Cancer Institute and Dr. Michael Ortiz, Memorial Sloan Kettering Cancer Center

Effort overview: This grant funds the manufacturing and distribution of an experimental drug, DT2216, for a clinical trial for fibrolamellar patients. The Foundation’s funding of the manufacturing costs of the drug was essential to ensure that the fibrolamellar-specific clinical trial could be launched.

Dialectic Therapeutics, Inc. is a Texas-based clinical stage biotechnology company focused on creating innovative new technologies to treat cancer. DT2216 is their first-in-class anticancer agent that targets a protein called BCL-XL, the most commonly over-expressed anti-apoptotic protein in cancer. Anti-apoptotic proteins help prevent programmed cell death (apoptosis) in cells, allowing them to survive longer than they normally would. They play a crucial role in cell survival and cancer development. By degrading BCL-XL, DT2216 can stimulate cancer cells to commit suicide or become more susceptible to chemotherapy. 

The supported clinical trial, sponsored by the Children’s Oncology Group (COG) and led by Dr. Michael Ortiz of the Memorial Sloan Kettering Cancer Center and Dr. Allison O’Neill from the Dana-Farber Cancer Institute, is open at major medical centers throughout the U.S. This phase 1/2 study, DT2216 in Combination with Irinotecan for Children, Adolescents and Young Adults with Relapsed or Refractory Solid Tumors: A Phase I Study with Phase II Feasibility Cohort for Fibrolamellar Carcinoma, tests the safety, side effects and best dose of DT2216 in combination with the chemotherapy agent, irinotecan. This study’s availability in a broad network of pediatric institutions should allow many FLC patients to join the trial at medical centers within reasonable distances from their homes.

This clinical effort is based on research conducted by Sanford Simon, PhD of Rockefeller University several years ago. The Rockefeller team observed that cancer cells from certain FLC patients could be killed by some chemotherapy drugs, including irinotecan. However, that susceptibility to the chemotherapy treatment correlated inversely with the FLC cells’ expression of BCL-XL. Fibrolamellar cells with low levels of BCL-XL were killed, while higher amounts of BCL-XL appeared to protect the cancer cells from the chemotherapy. Additional preclinical studies confirmed that the combination of DT2216 and irinotecan can synergize and shrink human FLC tumors with elevated levels of BCL-XL.

More information about the trial and its locations is available at clinicaltrials.gov/study/NCT06620302.

Timeframe: 2025 - 2027

Goal: Assess potential to induce immune response with a FLC therapeutic vaccine

Principal Investigator: Mark Yarchoan, MD and Marina Baretti, MD

Study overview: This grant allows Dr. Mark Yarchoan and Dr. Marina Baretti of Johns Hopkins University to keep JHU’s successful “peptide vaccine” clinical trial open to enrollment by fibrolamellar patients. 

In the study, patients receive a vaccine created to train the immune system to recognize and attack cells carrying the abnormal fusion protein that causes FLC. Because nearly all FLC tumors share this same fusion protein, the same “off-the-shelf” vaccine made from a small peptide representing the junction of the fused proteins can be used for all patients. During the clinical trial, the vaccine is administered alongside two immune checkpoint inhibitors (ICIs) already approved for use in other cancers (nivolumab and ipilimumab). 

Research published in Nature Medicine in November 2025 summarized the results of this clinical trial for the first 12 evaluable participants:

• The vaccine appears safe.
• 75% of participating patients mounted the desired immune response; all of these responders achieved some disease control (at least several months without tumor growth).
• One-third of responders (3 patients) experienced dramatic, long-lasting tumor shrinkage—and remain cancer-free.

An ultimate objective of the peptide vaccine study is to obtain FDA approval of a new, effective treatment regimen for FLC. The additional data provided by this expanded Phase 1 study will be crucial to determine the size (number of patients) and precise design of the Phase 2/3 clinical trial aimed at obtaining regulatory approval. It also will shed light on whether specific subgroups of patients are more likely to respond to the therapy.

Details of the trial and contact information can be found at: https://www.clinicaltrials.gov/ct2/show/NCT-04248569.

Timeframe: 2024 - 2029

Goals: Assess the potential of a FLC therapeutic vaccine to prevent disease recurrence

Principal Investigators: Juliane S. Walz, MD, CCU Translational Immunology, Department of Internal Medicine

Study Background and Overview: Various research efforts supported by FCF over the last 6 years have shown that immunotherapy approaches can save FLC patients' lives. The trial at Johns Hopkins for a peptide vaccine in combination with two checkpoint inhibitors demonstrated the effectiveness of that combination in some patients with advanced disease. Similarly, an ongoing clinical trial at Tübingen is testing the safety and effectiveness of another peptide vaccine in conjunction with a single checkpoint inhibitor in patients with advanced disease. This grant will extend the application of FLC vaccines to a new population – those deemed “cancer free” by RECIST criteria. It aims to directly address FLC’s high recurrence rate and the dilemma that has faced patients and their care teams for years – if a FLC patient is deemed “cancer free” at a point in time, what adjuvant treatments are appropriate? Because vaccines are a relatively low risk therapy, they could potentially serve that need.

A 2022 case study, published by the Tübingen team, illustrates how a FLC peptide vaccine helped a transplant patient who had suffered from successive recurrences. After treatment with a peptide vaccine, the patient's recurrences ended. That patient is still cancer free many years later.

This clinical trial, therefore, will assess the utility of the vaccine as adjuvant therapy in FLC patients, who, after surgery and/or other treatment, are free of cancer as judged by radiological scans. The goal is to significantly delay or entirely prevent relapse of the cancer. The vaccine will be administered alone, without additional immunotherapy or any other systemic agent.

Study Details: This FusionVAC22_02 study is directed from University Hospital Tübingen, Baden-Würtemberg, Germany. It is a Phase I, open-label, multicenter interventional clinical trial. The investigational drug is Fusion-VAC-XS15: DNAJB1::PRKACA fusion transcript-based peptide (FusionVAC-22). The vaccine will be applied subcutaneously, adjuvanted with the TLR1/2 ligand XS15 emulsified in Montanide ISA 51 VG.

It plans to enroll 20 subjects. The planned trial duration is 4 years. Pending approval by regulatory authorities, eligible subjects will be age 12 and above with histologically confirmed FLC or any other cancer with the DNAJB1::PRKACA fusion transcript, as documented by molecular analysis. Eligible subjects must have achieved a complete remission (CR) according to RECIST 1.1 by any of the following therapeutic measures:

• surgical procedures
• radiotherapy
• local therapeutic measures such as Transarterial Chemoembolization (TACE), or
• systemic treatment (e.g., chemotherapy).

The aim of the clinical trial is to evaluate the immunogenicity, safety, and toxicity of the vaccine in the study population. In addition to radiological assessment, regular testing for circulating tumor DNA (ctDNA) will be utilized to determine whether subjects have any residual cancer cells with the same DNA “signature” as the original tumor.

Timeframe: 2023 - 2028

Goals: Assess the potential of an inhibitor of glutamine metabolism (DRP-104; sirpiglenastat) in combination with an immune checkpoint inhibitor (durvalumab) as a treatment option for unresectable disease

Principal Investigators: Marina Baretti, MD and Mark Yarchoan, MD

Study overview: This phase Ib/2 clinical study, led by Dr. Marina Baretti and Dr. Mark Yarchoan of Johns Hopkins University, will test a new cancer treatment that capitalizes on FLC’s unique metabolism. Recent work from several research teams indicates that the DNAJB1-PRKACA fusion causes a metabolic rewiring of FLC tumor cells that makes them dependent on breaking down large amounts of the amino acid glutamine. This “glutamine addiction” leads to a nutrient-depleted tumor environment that is also enriched in immunosuppressive metabolites including ammonia. This could impair a patient’s ability to launch an effective immune response to the cancer.

The study plans to test the effectiveness of treating FLC patients with an inhibitor of glutamine metabolism (DRP-104; sirpiglenastat) in combination with an immune checkpoint inhibitor (durvalumab). The team’s hypothesis is that this treatment could deliver a “one-two punch” against FLC by:

• Directly attacking an important metabolic pathway of FLC tumors
• Restoring an immune supportive tumor environment, and therefore enabling a patient’s immune cells to attack the cancer.

The glutamine antagonist drug DRP-104 is being developed by Dracen Pharmaceuticals. Initial testing of DRP-104 in patients with solid tumors has already been completed. Dracen will provide DRP-104 for this FLC trial, as well as the necessary regulatory and operational support for the effort.

The phase 1b/2 clinical trial at Johns Hopkins will enroll patients diagnosed with unresectable or metastatic FLC whose disease progressed on prior immune therapy. The study will have two key aims:

1. Testing the safety and clinical activity of the DRP-104/durvalumab drug combination in children and adults with advanced FLC.
2. Determining whether the treatment suppresses glutamine-dependent processes and increases the number of activated FLC-specific T cells around FLC tumors.

Patient enrollment is anticipated to begin in late 4Q 2023. More information will be released once the trial receives all the necessary institutional and regulatory approvals.

Timeframe: 2022 - 2024

Goals: Accelerate development of potential clinical trial

Principal Investigator: Mark Yarchoan, MD

Study overview: This grant to Dr. Yarchoan is meant to support the development of a protocol for a potential clinical trial. In 2020, the Johns Hopkins team began a phase I clinical trial of an experimental vaccine containing a peptide (small segment of a protein) that corresponds to the junction region between the two parts of FLC’s characteristic chimeric protein. Patients enrolled in that trial also simultaneously received two FDA-approved checkpoint inhibitors – Opdivo (nivolumab) and Yervoy (ipilimumab).

This new effort is focused on designing an appropriate follow-up clinical study as soon as possible, to build on the learnings of the peptide vaccine effort and better understand factors that can limit the immune system’s ability to fight FLC.

Timeframe: 2020 - 2023

Goals: Assess the potential of the combination of nivolumab, fluorouracil, and interferon alpha-2b as a treatment option for unresectable disease

Principal Investigators: Sunyoung Lee, MD and Ahmed Kaseb, MD

Study overview: This phase I/II trial studies the side effects and how well the combination of nivolumab, fluorouracil, and interferon alpha-2b work for the treatment of fibrolamellar carcinoma (FLC) that cannot be removed by surgery. Immunotherapy with checkpoint inhibitors, such as nivolumab, may help the body’s immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Treatment with a combination of nivolumab, fluorouracil, and interferon alpha-2b may work better in treating unresectable fibrolamellar cancer compared to treatment with fluorouracil and interferon alpha-2b alone. This clinical trial stages the drug administration and includes the analysis of “before and after” patient biopsies (samples of tumor tissue) to better understand how the drug combination may affect patients’ immune responses to FLC.

Timeframe: 2019 - 2023

Goal: Assess potential to induce immune response with a FLC therapeutic vaccine

Principal Investigator: Mark Yarchoan, MD

Study overview: Many patients with FLC currently receive an immune checkpoint inhibitor off-label. These drugs “take the brakes off” the immune system, enhancing its ability to fight cancer. However, clinical experience suggests that they generally do not achieve strong anti-tumor responses from single checkpoint inhibitors. This study seeks to develop immunotherapy approaches to FLC that offer greater clinical benefit. In particular, it supports a clinical trial of an immune therapy for fibrolamellar carcinoma (FLC) at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, MD.

This clinical trial is the first test in patients of a combination of two checkpoint inhibitors (nivolumab and ipilimumab) plus a new vaccine designed to direct the immune response against FLC by targeting the DNAJ-PKAc fusion protein found in almost every case of this cancer. The fusion protein serves as a neoantigen, an abnormal protein found in the cancer but absent from normal cells. The selective component of the vaccine is a peptide (short segment of a protein) overlapping the junction between the DNAJ and PKAc segments of the fusion protein, which is consistent across FLC tumors. Thus, the vaccine could be harnessed by the immune system to recognize and eliminate cancer cells in any FLC patient with the characteristic gene fusion, in contrast to cancers for which a neoantigen vaccine must be personalized for each individual patient.

The primary goal of the study is to begin assessment of the safety and clinical activity of the FLC-vaccine in combination with nivolumab and ipilimumab in patients for whom complete surgical resection of the cancer is not possible. It also aims to determine if the combination of peptide vaccine and checkpoint inhibitors will promote induction and/or expansion of T cells that specifically recognize the DNAJ-PKAc fusion protein.

Trial subjects will be given an experimental vaccine containing a peptide (small segment of a protein) that corresponds to the junction region linking the two parts of the chimeric protein. They will simultaneously receive two FDA-approved drugs, Opdivo (nivolumab) and Yervoy (ipilimumab), that may enhance the immune response against FLC by overcoming “checkpoint” systems that can limit the immune system’s ability to fight a cancer.

Details of the trial and contact information can be found at: https://www.clinicaltrials.gov/ct2/show/NCT-04248569

Timeframe: 2014 - 2018

Goals: Develop and implement a clinical trial for combined liver and bone marrow transplantation as a treatment for liver-confined FLC

Principal Investigator: Ephraim Fuchs, MD

Study overview: This grant supported the development of a phase II, single center study to assess the feasibility and effectiveness of combining bone marrow transplantation and partial liver transplant from a matched living donor in patients with FLC.

The primary objective of this trial was to characterize recurrence-free survival at 1 year following bone marrow transplantation among recipients of prior partial liver transplantation from the same donor.

Under the proposed protocol, patients would have received a combination of:

• A living related donor partial liver transplantation
• Total body irradiation, and
• Bone marrow transplant from same donor.

The treatment was meant to apply to patients whose cancer remained confined to the liver but was too widespread to be removed by surgery or treated by a liver transplant from a deceased donor. These patients have a poor prognosis, with a median survival of 20 months. This protocol was designed to prolong the survival of these patients or perhaps even cure their disease. The purpose of the combined treatment was to reduce the risk of the cancer coming back after the liver transplant. The study team believed that bone marrow transplantation could reduce the risk of cancer relapse in two ways:

• Patients who have combined bone marrow and solid organ transplants may minimize the use of anti-rejection drugs, which inhibit the immune system from destroying cancer cells.
• The donor's bone marrow contains cells of their immune system, which can attack any cancer cells that remain after the liver transplant.

Details of the proposed trial approach can be found at: https://clinicaltrials.gov/study/NCT02702960

Results: The clinical study was withdrawn in 2018 before any patient enrollment. Most surgeons were concerned about management of the risks to the living donor as a consequence of such a high risk transplant approach.

Timeframe: 2010 - 2014

Goal: Assess potential of everolimus (RAD001) as a treatment option for FLC

Principal Investigator: Ghassan Abou-Alfa, MD

Study background and overview: At the time of this trial, the molecular drive of fibrolamellar, the DNAJB1-PRKACA fusion gene, had not been identified. However, several factors suggested that estrogen and estrogen-dependent pathways may play a role in FLC's pathogenesis, including:

• Case reports of gynecomastia as a presenting feature of FLC in young males
• Documentation of aromatase overexpression in FLC tumors
• The association of hyperestrogenic states including pregnancy and oral contraceptive use with FLC
• Demonstration of increased mammalian target of rapamycin (mTOR) activity in FLC tumors by immunohistochemical staining.

Consequently, on the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, the team hypothesized that suppression of estrogen and mTOR signaling could stop FLC tumor cells from growing and dividing. The combination of letrozole, a drug that prevents estrogen production, and everolimus (RAD001), a drug that controls the cancer cell signals had previously been shown to be active and safe in breast cancer patients. The team therefore proposed a study testing the effectiveness of estrogen deprivation therapy and mTOR inhibition in patients with advanced FLC.

The resulting phase II trial randomized patients into the following three arms:

• Arm A (everolimus),
• Arm B (letrozole/leuprolide) - estrogen deprivation therapy, or
• Arm C (everolimus/letrozole/leuprolide).

Upon disease progression, patients in arm A or B could transition to the everolimus/letrozole/leuprolide treatment.

Through this effort, FCF funded the first clinical trial of drugs aimed specifically at fibrolamellar carcinoma.  The trial was conducted Memorial Sloan Kettering, along with several other consortium members, including the University of California San Francisco, Johns Hopkins, and Dana Farber. Two major pharmaceutical companies donated the drugs investigated.  

Key findings: In total, 28 FLC patients were enrolled in this phase II trial. The study concluded that estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma. Neither approach improved patient outcomes.

The results of the clinical trial were published in The Oncologist in May 2020. Click here to read the published results of the study.