DRP-104 in Combination with Durvalumab for the Treatment of Patients with Metastatic or Unresectable Fibrolamellar Hepatocellular Carcinoma

Inclusion Criteria

• Patients must have histologically confirmed FLC that is metastatic or unresectable.
• Presence of DNAJB1-PRKACA fusion transcript, assessed by ribonucleic acid (RNA)-sequencing, deoxyribonucleic acid (DNA)-sequencing, or in situ hybridization in the archival tissue. NOTE: Patients without sufficient archival tissue may undergo a screening biopsy, which will be used to confirm the presence of the fusion transcript and will also fulfill the requirements of the baseline biopsy. In cases where confirmation of the fusion transcript leads to significant patient delay (e.g. > 3 weeks from screening), patients may enroll and begin study therapy pending confirmation of the DNAJB1-PRKACA fusion transcript. Patients later found not to have the DNAJB1-PRKACA fusion transcript will be replaced on study for all efficacy analyses.
• Patients must have demonstrated radiographic progression on current or after prior anti-PD(L)1 therapy.
• Age ≥ 12 years. NOTE: Subjects age ≥ 12 years but < 18 are eligible to enroll only after 3 evaluable 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 of ≤ 2 (Karnofsky ≥ 60%).
• Hemoglobin (HgB) ≥ 9.0 g/dL. Patients transfused to a hemoglobin ≥ 9.0 g/dL must maintain this hemoglobin for at least 1 week prior to first dose of DRP-104.
• Absolute neutrophil count ≥ 1,000/mcL.
• Platelets ≥ 75,000/mcL.
• Total bilirubin < 1.5 x upper limit of normal (ULN) (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN).
• Serum albumin ≥ 2.8 g/dL.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 upper limit of normal (ULN).
• International normalized ratio (INR) ≤ 1.6. Note: INR prolongation due to therapeutic anticoagulation for prophylaxis (e.g. atrial fibrillation) in patients without liver cirrhosis is an exception.
• Calculated creatinine clearance (CrCl) ≥ 40 mL/min using the modified Cockcroft-Gault.
• Patients must have measurable disease per RECIST 1.1.
• Willingness to provide tissue and blood samples for mandatory translational research. NOTE: Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator). Biopsies for the purpose of research will not be obtained in patients (age < 18). In the event that baseline biopsy is unsuccessful, subsequent biopsies will not be required and the subject will continue to be treated per study protocol.
• Evidence of post-menopausal status or negative serum pregnancy test for women of childbearing potential (WOCBP) (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]). Post-menopausal women and WOCBP. * NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then an ultrasound must be done to rule out pregnancy to enroll on trial. ** WOCBP must agree to follow instructions for method(s) of contraception: hormonal or barrier method of birth control, including male condom, female condom, or diaphragm with spermicidal gel; abstinence) from the time of enrollment for the duration of treatment with study drugs plus 120 days post study drug treatment completion. ** Men who are sexually active with WOCBP must agree to follow instructions for method (s) of contraception for the duration of treatment with study drug(s) plus 120 days post study drug treatment completion.
• Patient and/or patient’s parent or legal guardian must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

• Patients who have had chemotherapy or other systemic therapy or radiotherapy, as follows: * Patients who have had chemotherapy, biological cancer therapy, or radiation 21 days prior to the first dose of study drug. * Patients who have had surgery within 28 days of dosing of study drugs, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement. * Patients who have received other approved or study drugs or device within 21 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 investigational new drug (IND) sponsor.
• Patients with corrected QT (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.
• Known sensitivity to or history of allergic reactions attributed to compounds of similar chemical or biologic composition of DRP-104 or durvalumab.
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Patient has a pulse oximetry of < 92% on room air or is on supplemental home oxygen.
• Patients with active or untreated brain metastases or leptomeningeal metastases NOTE: Patients with previously treated brain metastases must have stable neurologic status and imaging following local therapy (surgery or radiation) for at least 4 weeks, with no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration (stable low dose dexamethasone allowed at discretion of IND sponsor).
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situation; or concurrent active malignancy requiring systemic therapy or expected to require active therapy within the clinical study period, or any other intercurrent illness that in the judgment of the investigator would limit compliance with study requirements or interfere with the interpretation of the therapy response.
• Pregnant women are excluded from this study because the agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued. NOTE: WOCBP or men who are sexually active with WOCBP who are unwilling to follow methods for contraception for the duration of the study and at least 120 days post study drug completion will not be permitted on study.
• Has a known history of human immunodeficiency virus (HIV) with AIDS or AIDS defining opportunistic infection within the last year prior to enrollment. * NOTE: HIV seropositive participants who are otherwise healthy and at low risk for AIDS-related outcomes could be considered eligible. HIV infected participants must be on anti-retroviral therapy (ART) with most recent CD4 count ≥ 350 cells/uL and undetectable HIV viral load. CD4 and viral load should be serially monitored as per standard of care by the participant's outpatient HIV provider. Potential eligibility for a specific HIV positive candidate should be evaluated and discussed with the principal investigator prior to any screening.
• Has active, hepatitis B or hepatitis C with the following exceptions. * Patients with chronic or acute hepatitis B virus (HBV) infection [as defined by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/ml)] must have disease controlled (HBV DNA < 500 IU/ml) prior to enrollment and have received antiviral therapy for at least 4 weeks prior to study enrollment. * Patients who test positive for anti-HBcAb with undetectable HBV DNA (< 10 IU/ml) do not require anti-viral therapy prior to enrollment, but HBV DNA levels should be monitored and antiviral therapy should be initiated if HBV DNA is detected (≥ 10 IU/ml). * Patients with history of hepatitis C infection may participate if they have completed curative antiviral treatment and have undetectable hepatitis C virus (HCV) viral load at the time of study enrollment. Additional testing for surveillance may be obtained as clinically indicated.
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, or gastrointestinal (GI) obstruction which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study.
• Patient is 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 other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements.
• Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 weeks prior to the first scheduled dose.
• Participants a with history of prior unacceptable and/or life-threatening toxicities attributed to anti-PD(L)1 therapy, except for toxicities that are unlikely to re-occur with standard countermeasures (e.g., endocrinopathy successfully managed hormone replacement therapy). NOTE: If the investigator assesses a drug-related toxicity (that requires discontinuation) to be related to anti- CTLA4 (i.e. not anti-PD(L)1) therapy, patients can be enrolled in the study.
• Has active autoimmune disease (not including immune related adverse events from prior immune checkpoint inhibitor) that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or is likely to interfere with the safety or efficacy of the trial therapy in the opinion of the treating investigator. NOTE: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant and liver transplant will be excluded. Instances where loss of the graft is not a clinical concern (such as dental bone grafts or skin grafts placed only to promote skin growth) can be approved by the principal investigator.
• Has a diagnosis of immunodeficiency.
• Patients requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of study drug administration. The following are exceptions to this criterion: * Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). * Physiologic replacement doses of systemic corticosteroids are permitted, doses not to exceed 10 mg/day of prednisone or its equivalent. * A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• Patients who have had either of the following procedures or medications within 4 weeks prior to initiation of study treatment: * Any live, attenuated vaccine. * Allergen hypo sensitization therapy in the last 2 weeks.