A DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Glutamine Antagonist DRP-104, Nivolumab, and Ipilimumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC)

Официальное название

A Phase 1b Study of a DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Glutamine Antagonist DRP-104, Nivolumab, and Ipilimumab for Patients With Advanced Stage Fibrolamellar Hepatocellular Carcinoma (FLC)

Обзор

The purpose of this study is to determine whether the combination of a neoantigen vaccine targeting the DNAJB1-PRKACA fusion kinase in combination with DRP-104, Nivolumab and Ipilimumab is safe and yields a clinically compelling antitumor activity measured as based on objective response rate (ORR, assessed by RECIST 1.1). Secondary objectives include progression-free survival (PFS) and overall survival (OS).

Вмешательства

• Препарат DNAJB1-PRKACA Peptide Vaccine
  1. Patients will receive treatment on Day 1, 8 and 15 of cycle 1 and on Day 1 of cycle 2, 3, and 4 (Prime Phase). Boost vaccinations will be administered every 3 cycles beginning from C5D1. 2. Drug: 0.3 mg DNAJB1-PRKACA peptide vaccine + 0.5 mg Poly-ICLC
• Препарат DRP-104
  1. Patients will receive treatment on Day 1, 4, 8, 11, 15, and 18 of cycle 1-4 (Prime Phase) then on Days 1, 4, 8, 11, 15, 18, 22 and 25 of each cycle starting on Day 1 of Cycle 5 (Boost/maintenance Phase). DRP-104 will be administered as a subcutaneous injection twice a week (BIW) on a continuous schedule for up to two years. 2. Drug: 145 mg
• Препарат Nivolumab
  1. Patients will receive treatment on Day 1 of each Cycle. Nivolumab 3mg/kg will be administered every 3 weeks as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycle 1-4 (Prime Phase). Nivolumab infusions will be administered as a flat dose of 480mg every 4 weeks starting on Day 1 of Cycle 5 (Boost/maintenance). 2. Drug: 3mg/kg and 480mg IV
• Препарат Ipilimumab
  1. Patients will receive treatment on Day 1 of Cycle 1-4 (Prime Phase). Ipilimumab (1 mg/kg) will be administered. Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10/+15min). 2. Drug: 1mg/kg IV

Первичные конечные точки

• Number of participants experiencing grade 3 or above drug-related toxicities [Срок оценки: 4 years]
• Objective response rate (ORR) using immune Response Evaluation Criteria for Solid Tumors (RECIST 1.1) [Срок оценки: 4 years]

Вторичные конечные точки (2)

• Progression-free Survival (PFS) number of months according to RECIST (1.1) criteria. [Срок оценки: 4 years]
• Overall survival (OS) of patients treated with study drug combination [Срок оценки: 4 years]

Критерии участия

Критерии включения

• Must have histologically confirmed FLC 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.
• Must have demonstrated radiographic progression on prior or current immunotherapy.
• Age ≥ 12 years.
• Patients < 18 years old must have a body weight ≥ 40 kg.
• ECOG (Eastern Cooperative Oncology Group) performance status of ≤2
• Patients must have adequate organ and marrow function defined by study-specified laboratory tests.
• Patients must have adequate kidney and liver function defined by study-specified laboratory tests.
• Must have measurable disease per RECIST 1.1
• Willingness to provide tissue and blood samples for mandatory translational research.
• Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test.
• For both Women and Men, must use acceptable form of birth control while on study.
• Ability to understand and willingness to sign a written informed consent document.

Критерии исключения

• 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.
• Must have had chemotherapy or other systemic therapy or radiotherapy, as follows:

• Patients who have had chemotherapy, biological cancer therapy, or radiation 14 days prior to the first dose of study drug.
• Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures.
• Patients who have received other approved or investigational agents or device within 28 days of the first dose of study drug.
• Patients who have not recovered from acute adverse events to grade ≤1 or baseline due to agents administered, with exception of grade 2 fatigue, rash, and endocrinopathy successfully managed hormone replacement therapy, or alopecia or stable neuropathy, unless approved by the IND Sponsor.
• Patients who 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 attributed to compounds of similar chemical or biologic composition of polyinosinic-polycytidylic acid (Poly-ICLC) and/or DRP-104 and/or nivolumab and/or ipilimumab.
• History of severe hypersensitivity reaction to any monoclonal antibody.
• Has an active autoimmune disease.
• Prior allogeneic stem cell transplantation or organ transplantation.
• Has a diagnosis of immunodeficiency.
• Systemic corticosteroids at immunosuppressive doses.
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• 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 active medical and/or psychiatric illness/social psychosocial problems that that would limit compliance with study requirements.
• 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.
• Pregnant or breastfeeding.
• Has a known history of Human Immunodeficiency Virus (HIV)/AIDS.
• Has active hepatitis B. Patients with chronic or acute HBV infection.
• Have had evidence of active or acute diverticulitis, intra-abdominal abscess, or GI obstruction which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study.
• Unwilling or unable to follow the study schedule for any reason.
• Patient is at the time of signing informed consent a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
• Evidence of clinical ascites.
• Patients with QTc prolongation > 470 ms according to Fridericia formula.
• Patients receiving potent inducers of CYP 3A4/5 (including but not limited to apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin and St. John's Wort) who cannot safely discontinue drug at least 14 days prior to Cycle 1 Day 1.
• Have had an allergen hyposensitization therapy within 2 weeks prior to initiation of study treatment.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Johns Hopkins SKCCC — Baltimore

Идентификаторы

NCT: NCT07430202 · J2622 · IRB00541955

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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