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

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ClinicalTrials.gov Identifier: NCT04248569
Recruitment Status : Recruiting
First Posted : January 30, 2020
Last Update Posted : August 12, 2021
Sponsor:
Collaborators:
Bristol-Myers Squibb
Fibrolamellar Cancer Foundation
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE January 28, 2020
First Posted Date  ICMJE January 30, 2020
Last Update Posted Date August 12, 2021
Actual Study Start Date  ICMJE April 21, 2020
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 5, 2021)
  • 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
  • Fold change in interferon-producing DNAJB1-PRKACA-specific cluster of differentiation 8 (CD8) T cells at 10 weeks [ Time Frame: Baseline and 10 weeks ]
    Evaluated by the fold change in interferon-producing DNAJB1-PRKACA-specific CD8 cells after vaccination at 10 weeks compare to pre-vaccination baseline.
  • Fold change in interferon-producing DNAJB1-PRKACA-specific cluster of differentiation 4 (CD4) T cells at 10 weeks [ Time Frame: Baseline and 10 weeks ]
    Evaluated by the fold change in interferon-producing DNAJB1-PRKACA-specific CD4 T cells after vaccination at 10 weeks compare to pre-vaccination baseline.
Original Primary Outcome Measures  ICMJE
 (submitted: January 28, 2020)
  • 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
  • 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.
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2020)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma
Official Title  ICMJE A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Fibrolamellar Hepatocellular Carcinoma (FLC)
Intervention  ICMJE
  • 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®
Study Arms  ICMJE Experimental: DNAJB1-PRKACA peptide vaccine, Nivolumab, and Ipilimumab
Interventions:
  • Drug: DNAJB1-PRKACA peptide vaccine
  • Drug: Nivolumab
  • Drug: Ipilimumab
Publications * O'Neill AF, Church AJ, Perez-Atayde AR, Shaikh R, Marcus KJ, Vakili K. Fibrolamellar carcinoma: An entity all its own. Curr Probl Cancer. 2021 Aug;45(4):100770. doi: 10.1016/j.currproblcancer.2021.100770. Epub 2021 Jul 1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 28, 2020)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2024
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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, DNA sequencing, or in situ hybridization 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Anna Ferguson, RN 410-614-7186 afergus1@jhmi.edu
Contact: Marina Baretti, MD 410-614-1058 mbarett1@jhu.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04248569
Other Study ID Numbers  ICMJE J19140
IRB00222681 ( Other Identifier: Johns Hopkins Medicine Institutional Review Board )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Fibrolamellar Cancer Foundation
Investigators  ICMJE
Principal Investigator: Mark Yarchoan, MD Johns Hopkins Medical Institution
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP