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DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04248569
Recruitment Status : Recruiting
First Posted : January 30, 2020
Last Update Posted : April 13, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
The primary objective of the trial is the safety and tolerability of administering a vaccine targeting the DNAJB1-PRKACA fusion kinase, in combination with nivolumab and ipilimumab in patients with unresectable or metastatic FLC and to assess the T-cell response.

Condition or disease Intervention/treatment Phase
Fibrolamellar Hepatocellular Carcinoma (FLC) Drug: DNAJB1-PRKACA peptide vaccine Drug: Nivolumab Drug: Ipilimumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma
Actual Study Start Date : April 10, 2020
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: DNAJB1-PRKACA peptide vaccine, Nivolumab, and Ipilimumab Drug: DNAJB1-PRKACA peptide vaccine
  1. Patient 1-3: DNAJB1-PRKACA peptide vaccine will be administered on Day 1, 8, 15 of cycle 1 and on Day 1 of cycle 2, 3, 4 and 5 (priming phase). Boost vaccinations will be administered every 3 cycles beginning from C6D1.
  2. Patient 4-12: DNAJB1-PRKACA peptide vaccine will be administered on Day 1, 8, 15 of cycle 1 and on Day 1 of cycle 2, 3 and 4 (priming phase). Boost vaccinations will be administered every 3 cycles beginning from C5D1.
  3. Drug: 0.3 mg DNAJB1-PRKACA peptide vaccine + 0.5mg Poly-ICLC
  4. Other Names: Hiltonol® (Poly-ICLC)
Other Name: Hiltonol® (Poly-ICLC)

Drug: Nivolumab
  1. Patient 1-3: Nivolumab 3mg/kg will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycle 2-5 during the priming phase. Boost/maintenance vaccinations will be administered as a flat dose of 480mg every 4 weeks starting on Day 1 of Cycle 6.
  2. Patient 4-12: Nivolumab 3mg/kg will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycle 1-4 during the priming phase. Boost/maintenance vaccinations will be administered as a flat dose of 480mg every 4 weeks starting on Day 1 of Cycle 5.
  3. Drug: 3mg/kg and 480mg IV
  4. Other Name: OPDIVO
Other Name: OPDIVO

Drug: Ipilimumab
  1. Patient 1-3: Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycles 2, 3, 4 and 5 of the study, every 3 weeks of the priming phase.
  2. Patient 4-12: Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycles 1, 2, 3 and 4 of the study, every 3 weeks of the priming phase.
  3. Drug: 1mg/kg IV
  4. Other Name: YERVOY®
Other Name: YERVOY®




Primary Outcome Measures :
  1. Number of participants experiencing study drug-related toxicities [ Time Frame: 4 years ]
    Number of participants experiencing study drug-related adverse events Grade 3 or higher as defined by CTCAE v5.0

  2. Fold change in interferon-producing DNAJB1-PRKACA-specific cluster of differentiation 8 (CD8) T cells at 12 weeks [ Time Frame: Baseline and 12 weeks ]
    Evaluated by the fold change in interferon-producing DNAJB1-PRKACA-specific CD8 cells after vaccination at 12 weeks compare to pre-vaccination baseline.

  3. Fold change in interferon-producing DNAJB1-PRKACA-specific cluster of differentiation 4 (CD4) T cells at 12 weeks [ Time Frame: Baseline and 12 weeks ]
    Evaluated by the fold change in interferon-producing DNAJB1-PRKACA-specific CD4 T cells after vaccination at 12 weeks compare to pre-vaccination baseline.


Secondary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: 4 years ]
    ORR is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) at any time during the study. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.

  2. iRECIST Objective response rate (iRORR) [ Time Frame: 4 years ]
    iRORR is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors (iRECIST 1.1) at any time during the study. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.

  3. Duration of response (DoR) [ Time Frame: 4 years ]
    Number of weeks from the start date of PR or CR (whichever response is recorded first) and subsequently confirmed to the first date of disease progression or death is documented per RECIST 1.1. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions.

  4. Disease control rate (DCR) [ Time Frame: 4 years ]
    DCR is defined as the number of patients achieving a complete response (CR) or partial response (PR) and stable disease (SD) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) at any time during the study. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.

  5. Progression-free survival (PFS) [ Time Frame: 4 years ]
    PFS is defined as the number of patients with disease progression (progressive disease [PD] or death due to any cause. Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20% increase in sum of diameters of target lesions, Stable Disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions. Estimation based on the Kaplan-Meier curve.

  6. Immune progression-free survival (irPFS) [ Time Frame: 4 years ]
    irPFS rate is defined as the number of patients with disease progression (PD or death due to any cause. Per immune-related response (irRC) criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in tumor burden compared with baseline, Progressive Disease (PD) is >20% increase in tumor burden compared with nadir, Stable Disease (SD) is <30% decrease in tumor burden compared with baseline or <20% increase in tumor burden compared to nadir. Estimation based on the Kaplan-Meier curve.

  7. Overall survival (OS) [ Time Frame: 4 years ]
    OS will be measured from date of first dose until death or end of follow-up (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 100 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must have histologically confirmed FLC (fibrolamellar hepatocellular cancer) that is metastatic or unresectable.
  • Presence of DNAJB1-PRKACA fusion transcript, assessed by RNA-sequencing in the archival tissue.
  • Age ≥12 years. Note: Subjects age ≥ 12 years but <18 are eligible to enroll only after 6 adult patients have enrolled on the study.
  • Patients < 18 years old must have a body weight ≥40 kg.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Patients must have adequate organ and marrow function defined by study-specified laboratory tests prior to initial study drug.
  • Patients must have measurable disease per RECIST 1.1.
  • Patients ≥ 18 years old must have an accessible non-bone tumor lesion from which serial core biopsy specimens can be obtained.
  • Must be willing to provide tissue and blood samples for mandatory translational research.
  • Woman of childbearing potential must have a negative pregnancy test and follow contraceptive guidelines as defined per protocol.
  • Men must use acceptable form of birth control while on study.
  • Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

  • Have had chemotherapy or other systemic therapy or radiotherapy, as follows:

    • Have had chemotherapy, biological cancer therapy, or radiation 14 days prior to the first dose of study drug.
    • Have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement.
    • Have received other approved or investigational agents or device within 28 days of the first dose of study drug.
    • Have not recovered from acute adverse events to grade ≤1 or baseline due to agents administered
  • Prior treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, etc.).
  • Have received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment
  • Known sensitivity to or history of allergic reactions to investigational drug (s).
  • Hypersensitivity reaction to any monoclonal antibody.
  • Has active autoimmune disease that has required systemic treatment in the past 2 years, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
  • Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoeitic stem cell transplant will be excluded.
  • Has a diagnosis of immunodeficiency.
  • Systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of study drug administration.
  • Symptomatic interstitial lung disease.
  • Has a pulse oximetry of <92% on room air or is on supplemental home oxygen.
  • Active or untreated brain metastases or leptomeningeal metastases.
  • Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Are pregnant or breastfeeding.
  • Infection with HIV or hepatitis B or C.
  • Have had evidence of active or acute diverticulitis, intra-abdominal abscess, or GI obstruction.
  • Unwilling or unable to follow the study schedule for any reason.
  • Any other sound medical, psychiatric, and/or social reason as determined by the Investigator.
  • Any illicit drugs or other substance abuse.
  • Clinically meaningful ascites.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04248569


Contacts
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Contact: Anna Ferguson, RN 410-614-7186 afergus1@jhmi.edu
Contact: Marina Baretti, MD 410-614-1058 mbarett1@jhu.edu

Locations
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United States, Maryland
Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21231
Contact: Anna Ferguson, RN    410-614-3644    afergus1@jhmi.edu   
Contact: Marina Baretti, MD    410-614-1058    mbarett1@jhu.edu   
Principal Investigator: Mark Yarchoan, MD         
Sub-Investigator: Marina Baretti, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
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Principal Investigator: Mark Yarchoan, MD Johns Hopkins Medical Institution
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT04248569    
Other Study ID Numbers: J19140
IRB00222681 ( Other Identifier: Johns Hopkins Medicine Institutional Review Board )
First Posted: January 30, 2020    Key Record Dates
Last Update Posted: April 13, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
DNAJB1-PRKACA Peptide Vaccine
Nivolumab
Ipilimumab
Anti-PD-1 (receptor blocking antibody)
Anti-CTLA-4 (receptor blocking antibody)
Neoantigen Vaccines
Cancer Vaccines
Immunotherapy
Fibrolamellar Hepatocellular Cancer (FLC)
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Nivolumab
Ipilimumab
Poly ICLC
Antineoplastic Agents, Immunological
Antineoplastic Agents
Interferon Inducers
Immunologic Factors
Physiological Effects of Drugs