Clinical trial NCT04248569: DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma
Official title: A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Fibrolamellar Hepatocellular Carcinoma (FLC)
Keywords: 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)
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Fibrolamellar Cancer Foundation
name: National Cancer Institute (NCI)
First posted: 2020-01-30
Enrollment: 56
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 with non-FLC solid tumors and to assess the T-cell response.


Eligibility criteria: Inclusion Criteria:

* Cohort A and B: Must have histologically confirmed FLC (fibrolamellar hepatocellular cancer) that is metastatic or unresectable.
* Cohort C: Patients with histologically proven metastatic or unresectable DNAJB1-PRKACA fusion transcript positive solid tumor malignancies, non-FLC solid tumors.
* Cohort A and B: Age \> 12 years. Note: Subjects age \> 12 years but \<18 are eligible to enroll only after 6 adult patients have enrolled on the study.
* Cohort A and B: Patients \< 18 years old must have a body weight ≥40 kg.
* Cohort C: Patients must be Age ≥ 18 years.

All Cohorts:

* • Presence of DNAJB1-PRKACA fusion transcript, assessed by RNA-sequencing, DNA-sequencing, or in situ hybridization in the archival tissue.
* ECOG performance status of ≤2 (Karnofsky ≥60%)
* Patients must have adequate liver, kidney 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:

* Cohort A and C: Patients with a history of prior treatment with checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, anti-CTLA-4, or anti-LAG-3 antibodies. NOTE: Prior therapy with interferon-alpha is allowed.
* Cohort B: Participants a with history of unacceptable, life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment, any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after endocrinopathy).

All Cohorts:

* 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.
* 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.

Primary outcomes:
measure: Number of participants experiencing study drug-related toxicities
timeFrame: 2.5 years
measure: Fold change in interferon-producing DNAJB1-PRKACA-specific cluster of differentiation 8 (CD8) T cells at 10 weeks
timeFrame: Baseline and 10 weeks
measure: Fold change in interferon-producing DNAJB1-PRKACA-specific cluster of differentiation 4 (CD4) T cells at 10 weeks
timeFrame: Baseline and 10 weeks
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: 4 years
measure: Duration of response (DoR)
timeFrame: 4 years
measure: Disease control rate (DCR)
timeFrame: 4 years
measure: Progression-free survival (PFS)
timeFrame: 4 years
measure: Overall survival (OS)
timeFrame: 4 years
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center
state: Maryland
Study officials:
affiliation: Johns Hopkins Medical Institution
name: Mark Yarchoan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Short SS, Kastenberg ZJ, Wei G, Bondoc A, Dasgupta R, Tiao GM, Watters E, Heaton TE, Lotakis D, La Quaglia MP, Murphy AJ, Davidoff AM, Mansfield SA, Langham MR, Lautz TB, Superina RA, Ott KC, Malek MM, Morgan KM, Kim ES, Zamora A, Lascano D, Roach J, Murphy JT, Rothstein DH, Vasudevan SA, Whitlock R, Lal DR, Hallis B, Butter A, Baertschiger RM, Lapidus-Krol E, Putra J, Tracy ER, Aldrink JH, Apfeld J, Le HD, Park KY, Rich BS, Glick RD, Fialkowski EA, Utria AF, Meyers RL, Riehle KJ. Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study. Cancer. 2022 Jul 15;128(14):2786-2795. doi: 10.1002/cncr.34256. Epub 2022 May 13.
citation: 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.