Important Safety Information Including Boxed Warning
What is HEPZATO KIT?
HEPZATO KIT consists of a closed circuit of catheters and proprietary filtration technology utilized to deliver HEPZATO (melphalan) to the hepatic artery and to lower the concentration of melphalan in the blood before it is returned to systemic circulation.
HEPZATO (melphalan) for injection is a component of the HEPZATO KIT Hepatic Delivery System (HDS) for intra-arterial use. Initial U.S. approval: 1964
WARNING: SEVERE PERI-PROCEDURAL COMPLICATIONS, MYELOSUPPRESSION
See full prescribing information for complete boxed warning.
- Severe peri-procedural complications including hemorrhage, hepatocellular injury, and thromboembolic events may occur with intra-hepatic administration of HEPZATO. Assess patients for these adverse reactions during and for 72 hours following administration of HEPZATO.
- HEPZATO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy called the HEPZATO KIT REMS.
- Myelosuppression with resulting severe infection, bleeding, or symptomatic anemia may occur with HEPZATO. Monitor hematologic laboratory parameters and delay additional cycles of HEPZATO therapy until blood counts have improved.
INDICATIONS AND USAGE
HEPZATO is an alkylating drug indicated as a liver-directed treatment for adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.
DOSAGE AND ADMINISTRATION
HEPZATO, a component of the HEPZATO KIT, is administered by intra-arterial infusion into the hepatic artery (see instructions for use [IFU]). The recommended dose is 3 mg/kg based on ideal body weight (see Table 1), with a maximum absolute dose of 220 mg during a single HEPZATO treatment. The drug is infused over 30 minutes followed by a 30-minute washout period (see IFU). Treatments should be administered every six (6) to eight (8) weeks but can be delayed until recovery from toxicities and as per clinical judgement.
DOSAGE FORMS AND STRENGTHS
For injection: HEPZATO includes 50 mg freeze-dried (lyophilized) melphalan powder per vial in five (5) single dose vials, intended for reconstitution with the supplied diluents.
CONTRAINDICATIONS
- Active intracranial metastases or brain lesions with a propensity to bleed
- Liver failure, portal hypertension, or known varices at risk for bleeding
- Surgery or medical treatment of the liver in the previous 4 weeks
- Active cardiac conditions including, but not limited to, unstable coronary syndromes (unstable or severe angina or myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease
- History of allergies or known hypersensitivity to melphalan or a component or material utilized within the HEPZATO KIT including natural rubber latex, heparin, and severe hypersensitivity to iodinated contrast not controlled by antihistamines and steroids
WARNINGS AND PRECAUTIONS
- Hypersensitivity reactions, including anaphylaxis, have occurred in patients who received an intravenous (IV) formulation of melphalan. Immediately terminate hepatic arterial melphalan infusion for hypersensitivity reactions and administer supportive care
- Gastrointestinal disturbances such as nausea and vomiting, abdominal pain and diarrhea are common
- Carcinogenic/Mutagenic effects: Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating drugs (including melphalan). Melphalan has been shown to cause chromatid or chromosome damage in humans
- Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception
- Infertility: Melphalan-based chemotherapy regimens have been reported to cause suppression of ovarian function in premenopausal women and testicular suppression in men
ADVERSE REACTIONS
Most common (≥20%) adverse reactions or laboratory abnormalities are thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased alkaline phosphatase, and dyspnea.
To report SUSPECTED ADVERSE REACTIONS, contact Delcath at 1-833-632-0458 and www.Delcath.com or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
- HEPZATO should not be used in patients < 35 kg
- Lactation: Advise not to breastfeed
Your Title Goes Here
HEPZATO KIT:
First and Only FDA-Approved Whole Liver Directed Therapy1
HEPZATO KIT is a unique treatment that delivers high-dose chemotherapy to the entire liver while limiting systemic exposure.1-3
Isolation
Isolating the liver blood supply allows for the benefits of high-dose melphalan while reducing systemic toxicity3,4
Saturation
A 30-minute infusion of high-dose melphalan saturates the liver, effectively delivering treatment to the entire organ1,3
Filtration
A 30-minute washout period limits systemic drug exposure (mean [SD] filter efficiency of 82.7% [14.4%] for the total filtration period)1
Melphalan mechanism of action1,5,6
How melphalan works
Melphalan acts by introducing interstrand cross-links into DNA. It is active against both resting and rapidly dividing tumor cells.1
You May Know Melphalan But Not Like This
HEPZATO KIT delivers the potency of high-dose melphalan directly into the liver. Melphalan causes rapid and irreversible DNA damage that results in cancer cell death.1
- Melphalan has been approved and used in the United States since 19641
Delivering an Innovative Treatment With a Well-Trained Team
HEPZATO KIT is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the HEPZATO KIT REMS.
Treatment with HEPZATO KIT involves training and a team approach. All procedure team members complete a REMS training. HEPZATO KIT procedure team members include2,a:
Interventional radiologist
Leads and performs the vascular interventional procedure2
Perfusionist
Anesthesiologist
Other clinical team members involved with HEPZATO KIT treatment include the medical/surgical oncologist, pharmacist, chemotherapist, and intensivist.2
Medical/surgical oncologist
Pharmacist
Chemotherapist
Intensivist
FOCUS Study Highlights
What was the FOCUS Study?
FOCUS was a multicenter, open-label trial that evaluated the efficacy and safety of melphalan delivered with the HEPZATO KIT in patients with unresectable metastatic uveal melanoma (mUM) predominately involving the liver.1
- Primary efficacy end point: Objective response rate (ORR)1
- Key secondary end point: Duration of response (DoR)1
More Than 1/3 of Patients Responded to Treatment With HEPZATO KIT1
ORR reported in FOCUS was 36.3% (n = 33)1
- Complete response (CR): 7.7% (n = 7)1
- Partial response (PR): 28.6% (n = 26)1
Median DoR in responders (n = 33) was 14 months1,c
ORR (CR or PR) in FOCUS1
Responders in FOCUS trial (n = 33)1
CR: Disappearance of all target lesionsa
PR: ≥30% Decrease in the sum of the long axis diameter of tumor target lesionsb
aAny pathological lymph nodes (target or nontarget) must be <10 mm in short-axis diameter. For nontarget lesions, disappearance of all nontarget lesions and normalization of tumor marker level.7
bUsing the baseline sum as reference.7
cCalculated using Kaplan-Meier method.1
FOCUS Study Design1
Study patients
95 Patients were enrolled into the HEPZATO KIT arm; 91 patients received treatment.1,a
Key exclusion criteria1
- Metastases occupying ≥50% of the liver parenchyma
- Unable to undergo general anesthesia
- ECOG PS ≥2
- Platelet count <100,000/μL
- Absolute neutrophil count <1500/μL
- Hemoglobin level <10 g/dL
- Child-Pugh class B or C cirrhosis
- Hepatitis B or C infection
ECOG PS, Eastern Cooperative Oncology Group performance status.
Treatment schedule
Patients received a dose of 3 mg/kg of melphalan using the HEPZATO KIT every 6 to 8 weeks for up to 6 treatment cycles.1,a
- Patients received a median of 4 treatment cycles (range, 1-6 cycles)
- The maximum of 6 treatment cycles was received by 37% of the 91 treated patients
aBased on ideal body weight (IBW; maximum total dose, 220 mg).
Want to know more about the FOCUS Study?
HEPZATO KIT: Demonstrated Safety and Tolerability1
Most common adverse events (>30% of patients)1
- Nausea
- Fatigue
- Musculoskeletal pain
- Abdominal pain
- Vomiting
All adverse events observed at a frequency of >10% in patients treated with HEPZATO KIT (N = 95)1
aRepresents a composite of multiple, related preferred terms.
Serious adverse events occurred in 45% of patients who received treatment with HEPZATO KIT1
Serious adverse events occurring in ≥2% of patients were thrombocytopenia (10%), neutropenia (8%), febrile neutropenia (7%), platelet count decreased (6%), leukopenia (4.2%), cardiac arrest (3.2%), neutrophil count decreased (2.1%), hypoxia (2.1%), pleural effusion (2.1%), pulmonary edema (2.1%), and deep vein thrombosis (2.1%).1
Fatal adverse events occurred in 3 patients (3.2%) who were treated with HEPZATO KIT; these included cardiac arrest, acute hepatic failure, and bacterial peritonitis and were deemed not to be related to HEPZATO KIT treatment.1,8
HEPZATO KIT treatment was permanently discontinued because of adverse events in 18% of patients, with neutropenia being the most common reason (3.2%).1
Frequently Asked Questions
References:
1. HEPZATO KIT. Package insert. Delcath Systems, Inc. 2023. 2. HEPZATO KIT. Instructions for use. Delcath Systems, Inc. 2023. 3. Quadri HS, Payabyab EC, Chen DJ, Figg W, Hughes MS. Percutaneous hepatic perfusion with melphalan for unresectable liver metastasis. Hepatoma Res. 2016;2:197-202. 4. Ferrucci PF, Cocorocchio E, Bonomo G, Varano GM, Della Vigna P, Orsi F. A new option for the treatment of intrahepatic cholangiocarcinoma: Percutaneous hepatic perfusion with CHEMOSAT delivery system. Cells. 2021;10(1):70. 5. Rycenga HB, Long DT. The evolving role of DNA inter-strand crosslinks in chemotherapy. Curr Opin Pharmacol. 2018;41:20-26. 6. Ramnani D. Metastatic malignant melanoma. WebPathology, LLC. Accessed November 9, 2023. https://www.webpathology.com/image.asp?case=243&n=30. 7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 8. Delcath Systems Inc. Data on file. 2.5 Clinical overview: Melphalan/HDS; hepatic-dominant ocular melanoma. 2022. 9. Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: Epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 2017;11:279-289. 10. Eschelman DJ, Gonsalves CF, Sato T. Transhepatic therapies for metastatic uveal melanoma. Semin Intervent Radiol. 2013;30(1):39-48. 11. Harbour JW. A prognostic test to predict the risk of metastasis in uveal melanoma based on a 15-gene expression profile. Methods Mol Biol. 2014;1102:427-440.
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