Cancer Vaccine + Nivolumab + Ipilimumab for Liver Cancer

Overseen By Colleen Apostol, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Checkpoint inhibitors, Monoclonal antibodies

Disqualifiers: Autoimmune disease, Immunodeficiency, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 10 weeks

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating certain types of liver cancer and other tumors using a combination of a cancer vaccine (DNAJB1-PRKACA Fusion Kinase Peptide Vaccine) and two immune-boosting drugs, nivolumab and ipilimumab. The main goal is to assess the safety and tolerability of this treatment while evaluating its ability to activate the body's T-cells (a type of immune cell). The trial targets individuals with liver cancer that cannot be surgically removed or has metastasized, as well as those with other solid tumors exhibiting a specific genetic marker (DNAJB1-PRKACA fusion). Candidates may qualify if they have these conditions and have not previously received certain immune therapies. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that you should not have had chemotherapy, biological cancer therapy, or radiation within 14 days before the first dose of the study drug. It's best to discuss your current medications with the trial team to get specific guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the DNAJB1-PRKACA fusion kinase peptide vaccine is initially safe and beneficial in early studies. This vaccine targets a specific protein found in some liver cancers.

Nivolumab, an immune therapy tested in liver cancer patients, caused serious immune-related side effects in about 21% of patients. When combined with another immune therapy, Ipilimumab, 17% of patients experienced serious liver-related side effects. Both Nivolumab and Ipilimumab have proven effective in treating liver cancer and have a known safety profile.

Overall, while these treatments show promise, they can have significant side effects. Those considering joining a clinical trial should discuss the potential benefits and risks with a healthcare professional. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a novel approach to tackling liver cancer, especially fibrolamellar carcinoma (FLC). Unlike traditional treatments like surgery, chemotherapy, or radiofrequency ablation, this combination uses a DNAJB1-PRKACA fusion kinase peptide vaccine alongside nivolumab and ipilimumab, which are types of immunotherapy. These drugs work by harnessing the body's immune system to recognize and attack cancer cells more effectively. This method is particularly promising because it targets cancer cells in a more personalized manner, potentially leading to better outcomes for patients with this rare type of liver cancer.

What evidence suggests that this trial's treatments could be effective for liver cancer?

This trial will evaluate the combination of the DNAJB1-PRKACA peptide vaccine with immune-boosting drugs, nivolumab and ipilimumab, for liver cancer. Studies have shown that targeting the DNAJB1-PRKACA fusion kinase, a specific protein change in fibrolamellar hepatocellular carcinoma (FLC), with a vaccine shows early signs of safety and potential effectiveness. Research suggests that combining this vaccine with nivolumab and ipilimumab could enhance the body's ability to combat cancer. Previous studies with these drugs in liver cancer have shown they can shrink tumors or even eliminate them in some patients, leading to longer survival. Together, these treatments aim to enhance the immune system's ability to attack cancer cells, offering hope for those with liver cancers that cannot be surgically removed or have spread to other parts of the body. ^{1 2 4 6 7}

Who Is on the Research Team?

Mark Yarchoan, MD

Principal Investigator

Johns Hopkins Medical Institution

Are You a Good Fit for This Trial?

This trial is for individuals with a rare liver cancer called fibrolamellar hepatocellular carcinoma (FLC) that can't be removed by surgery or has spread. Participants must be over 12 years old, weigh at least 40 kg if under 18, and have a tumor that can be biopsied. They need to have good organ function and performance status, not be on certain medications or treatments recently, and agree to use birth control.

Inclusion Criteria

Ability to understand and willingness to sign a written informed consent document.

My cancer has a specific genetic change known as DNAJB1-PRKACA fusion.

My cancer is advanced, cannot be surgically removed, and tests positive for a specific genetic change.

Exclusion Criteria

I haven't taken high-dose steroids or other immune-weakening drugs in the last week.

Have received other approved or investigational agents or device within 28 days of the first dose of study drug.

The doctor will decide if there are any other medical, mental health, or social reasons that make it unsuitable for you to participate in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the DNAJB1-PRKACA peptide vaccine in combination with nivolumab and ipilimumab

10 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

What Are the Treatments Tested in This Trial?

Interventions

• DNAJB1-PRKACA Fusion Kinase Peptide Vaccine
• Ipilimumab
• Nivolumab

Trial Overview The trial tests the safety of a new vaccine targeting DNAJB1-PRKACA fusion kinase in combination with two immunotherapy drugs: Nivolumab and Ipilimumab. It aims to see how well patients' T-cells respond to this treatment regimen for advanced FLC.

How Is the Trial Designed?

Group I: R- Enrollment: DNAJB1-PRKACA peptide vaccine, Nivolumab, and Ipilimumab Experimental Treatment 3 Interventions

Re-enrolling patients: Patients previously treated with the vaccine targeting the DNAJB1-PRKACA fusion kinase in combination with nivolumab and ipilimumab, who, in the opinion of the principal investigator, had clinical or radiological benefits. Re-enrolling patients who come off treatment ≤ 12 months from last dose may resume therapy at the study timepoint that they stopped study therapy. Patients who came off study therapy \> 12 months of last dose (i.e. to pursue alternative therapies (for example, surgical debulking), or after completion of the 2 years of study therapy), may restart study therapy at C1D1. In both cases, if the investigator assesses a drug-related toxicity to be related to anti-CTLA4 (ie. not anti-PD(L)1) therapy, patients can be enrolled in the study with nivolumab plus FLC peptide vaccine only.

Group II: DNAJB1-PRKACA peptide vaccine, Nivolumab, and Ipilimumab Experimental Treatment 3 Interventions

Cohort A: Patients with FLC cancer with no prior checkpoint inhibitor treatment. Cohort B: Patients with FLC cancer with prior checkpoint inhibitor treatment. Cohort C: Patients with non-FLC cancer (solid tumors) with prior checkpoint inhibitor treatment eligible.

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Fibrolamellar Cancer Foundation

Collaborator

Trials

3

Recruited

80+

Fibrolamellar Cancer Foundation

Collaborator

Trials

4

Recruited

110+

Published Research Related to This Trial

A clinical trial using cancer-specific peptide vaccines derived from RNF43 and TOMM34, combined with UFT and Leucovorin, was well tolerated in patients with advanced colorectal cancer, showing no serious adverse events.

Patients who developed cytotoxic T lymphocyte (CTL) responses against the peptides had long-term survival, indicating the potential efficacy of these vaccines in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment outcome of peptide vaccination for advanced colorectal cancer]. Sugiura, F., Inoue, K., Kogita, A., et al.[2020]

The four-peptide vaccination for advanced biliary tract cancer was well tolerated by patients, with no severe adverse events (grade 3 or 4) reported, indicating a favorable safety profile.

Among the nine patients treated, six showed clinical responses and seven exhibited peptide-specific T-cell immune responses, with median progression-free survival and overall survival of 156 and 380 days, respectively, suggesting potential efficacy of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Vaccination with Multiple Peptides Derived from Cancer-Testis Antigens Can Maintain a Specific T-cell Response and Achieve Disease Stability in Advanced Biliary Tract Cancer. Aruga, A., Takeshita, N., Kotera, Y., et al.[2020]

The VEGFR-targeted peptide vaccines were safe for patients with unresectable hepatocellular carcinoma (HCC), with no severe adverse events reported during the study involving 22 patients.

The vaccines successfully induced specific immune responses in a majority of patients, leading to improved progression-free survival (PFS) in those with strong immune responses, although overall survival rates did not show statistically significant differences compared to the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase I / II study of vascular endothelial growth factor receptor peptide vaccines for patients with hepatocellular carcinoma. Yoshimaru, Y., Nagaoka, K., Tanaka, K., et al.[2023]

The multi-target vaccine composed of peptides from cancer-testis antigens and VEGFRs was well-tolerated in a Phase I trial with 9 patients suffering from advanced pancreatic cancer, showing no severe adverse events.

Four out of nine patients experienced clinical benefits, with median progression-free survival of 90 days and overall survival of 207 days, indicating potential efficacy of the vaccine in this difficult-to-treat population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunological responses to a multi-peptide vaccine targeting cancer-testis antigens and VEGFRs in advanced pancreatic cancer patients. Okuyama, R., Aruga, A., Hatori, T., et al.[2021]

In a phase I trial involving 16 patients with pancreatic ductal adenocarcinoma (PDAC), the individualized neoantigen vaccine autogene cevumeran was found to be tolerable and successfully induced high levels of neoantigen-specific T cells in half of the patients, suggesting a promising immune response.

Patients who developed vaccine-expanded T cells had significantly longer recurrence-free survival (not reached) compared to those who did not, indicating that the vaccine may help delay the recurrence of PDAC when combined with atezolizumab and chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Rojas, LA., Sethna, Z., Soares, KC., et al.[2023]

The phase I clinical trial involving 18 patients with advanced colorectal cancer demonstrated that a combination vaccine using multiple peptides was well tolerated, with no severe systemic adverse events reported.

The treatment induced a dose-dependent immune response, with patients showing better outcomes (median overall survival of 27.8 months) when specific cytotoxic T lymphocytes were activated, highlighting the potential efficacy of this peptide-based vaccine approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome. Hazama, S., Nakamura, Y., Takenouchi, H., et al.[2021]

The DNAJB1-PRKACA fusion transcript is identified as the main driver of fibrolamellar hepatocellular carcinoma, and specific neoantigens derived from this fusion can effectively stimulate CD8+ and CD4+ T cell responses, indicating a potential target for immunotherapy.

In a case study of a patient with recurrent disease, vaccination with DNAJB1-PRKACA-derived peptides led to a strong and lasting T cell response, resulting in over 21 months of relapse-free survival, showcasing the efficacy of this targeted immunotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. Bauer, J., Köhler, N., Maringer, Y., et al.[2022]

A clinical trial using vaccines targeting specific cancer peptides (RNF43 and TOMM34) in combination with tegafur-uracil/Leucovorin (UFT/LV) for advanced colorectal cancer showed good tolerance and no adverse events.

Patients who developed cytolytic T-lymphocyte (CTL) responses to both RNF43 and TOMM34 had the highest long-term survival rates, indicating the potential effectiveness of these targeted vaccines in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical study of Peptide-cocktail vaccination with tegafur-uracil/leucovorin for advanced colorectal cancer]. Sugiura, F., Inoue, K., Okuno, K., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11007196/

FusionVAC22_01: a phase I clinical trial evaluating ... The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), ...

2. jitc.bmj.com jitc.bmj.com/content/11/Suppl_1/A733

641 A pilot study of a DNAJB1-PRKACA fusion kinase ... This first-in human study provides initial evidence of safety and clinical efficacy of a vaccine targeting the DNAJB1-PRKACA fusion plus immune checkpoint ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04248569

NCT04248569 | DNAJB1-PRKACA Fusion Kinase Peptide ... A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma.

4. nature.com nature.com/articles/s41467-022-33746-3

The oncogenic fusion protein DNAJB1-PRKACA can be ... The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies.

5. fibrofoundation.org fibrofoundation.org/flc-research/a-pilot-study-of-a-dnajb1-prkaca-fusion-kinase-peptide-vaccine-combined-with-nivolumab-and-ipilimumab-for-patients-with-fibrolamellar-hepatocellular-carcinoma/

A pilot study of a DNAJB1-PRKACA fusion kinase peptide ... The trial investigated the potential effectiveness of a targeted vaccine against FLC's DNAJ-PKAc driver when combined with the checkpoint inhibitors nivolumab ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04248569

NCT04248569 | DNAJB1-PRKACA Fusion Kinase Peptide ... The primary objective of the trial is the safety and tolerability of administering a vaccine targeting the DNAJB1-PRKACA fusion kinase, in combination with ...

7. fibrofoundation.org fibrofoundation.org/research/FCF-research-priorities/funded-clinical-trials/

Funded clinical trials 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 ...