Posology : מינונים

4.2     Posology and method of administration

KIMMTRAK should be administered under the direction and supervision of a physician experienced in the use of anti-cancer agents and who is prepared to manage cytokine release syndrome in an environment where full resuscitation facilities are immediately available. Hospitalisation is recommended for at least the first three infusions of KIMMTRAK (see section 4.4).

Patients treated with KIMMTRAK must have HLA-A*02:01 genotype determined by any validated HLA genotyping assay.

Posology

The recommended dose of KIMMTRAK is 20 micrograms on Day 1, 30 micrograms on Day 8, 68 micrograms on Day 15, and 68 micrograms once every week thereafter (see section 6.6). Treatment with KIMMTRAK should be continued while patient is deriving clinical benefit and in the absence of unacceptable toxicities (see section 5.1).

Premedication

To minimize the risk of hypotension associated with cytokine release syndrome (CRS), intravenous fluids should be administered prior to starting KIMMTRAK infusion based on clinical evaluation and the volume status of the patient.
For patients with preexisting adrenal insufficiency on maintenance systemic corticosteroids, adjusting the corticosteroid dose should be considered to manage the risk of hypotension.

Dose adjustments

No dose reductions of KIMMTRAK are recommended. KIMMTRAK should be withheld or discontinued to manage adverse reactions as described in Table 1 and Table 2.

If CRS is suspected, the symptoms should be identified and promptly managed according to recommendations in Table 1. See Table 2 for management guidelines for acute skin reactions.

Table 1: CRS grading and management guidance
CRS grade*                                             Management
Grade 1                                     •             Continue treatment and provide symptomatic Temperature ≥ 38 °C                                       support. Monitor for escalation in CRS No hypotension or hypoxia                                 severity.

Grade 2                                              •   Continue treatment and administer bolus Temperature ≥ 38 °C                                      intravenous fluids and oxygen by low flow nasal canula or blow-by oxygen as needed.
Hypotension that responds to fluids and does not require vasopressors                             •   If hypotension and hypoxia do not improve within 3 hours or CRS worsens proceed as
Oxygen requirement includes low flow nasal               for Grade 3 CRS - Administer cannula (delivery of oxygen ≤ 6 L/min) or                premedication with systemic corticosteroid blow-by                                                  prior to next dose, followed by close monitoring in a hospital setting (see
"Warnings and precautions").

•   For Grade 2 CRS that is persistent (lasting
2--3 hours) or recurrent (occurrence of ≥
Grade 2 CRS with more than one dose),
administer corticosteroid premedication (e.g.
dexamethasone 4 mg or equivalent) at least
30 minutes prior to next dose
Grade 3                                              •   Withhold KIMMTRAK until CRS and Temperature ≥ 38 °C                                      sequelae have resolved 
Require a vasopressor with or without                • Administer high-dose intravenous vasopressin                                            corticosteroid (e.g. 2 mg/kg/day methylprednisolone or equivalent).
Require high flow nasal cannula (delivery of oxygen > 6 L/min), face mask or non-rebreather       • Administer tocilizumab as needed mask or Venturi mask                                   - Patient weight ≤ 30 kg: 12 mg/kg intravenously over 1 hour
- Patient weight ≥ 30 kg: 8 mg/kg intravenously over 1 hour (maximum dose
800 mg)

• Resume KIMMTRAK at same dose level
(i.e., do not escalate if Grade 3 CRS occurred during initial dose escalation; resume escalation once dosage is tolerated)


• For Grade 3 CRS, administer corticosteroid premedication (e.g. dexamethasone 4 mg or equivalent) at least 30 minutes prior to next dose

Grade 4                                              • Permanently discontinue KIMMTRAK Temperature ≥ 38 °C
• Administer intravenous corticosteroid (e.g.,
Require multiple vasopressors (excluding               2 mg/kg/day methylprednisolone or vasopressin)                                           equivalent)
Requiring positive pressure (e.g. CPAP,
BiPAP, intubation and mechanical ventilation).

* Based on American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading of CRS criteria (Lee et. al 2019).



Table 2: Recommended management and dose modifications for acute skin reactions Adverse reactions          Severitya                      Management
Acute skin reactions     Grade 2                  • Withhold KIMMTRAK until Grade (see section 4.4)                                    ≤ 1 or baseline.

• Administer antipruritic regimen
(e.g., non-sedating long-acting antihistamine)

• Administer topical corticosteroid treatment for symptomatic rash that does not respond to anti-pruritic regimen.
• For persistent symptoms,
administer systemic steroids

•   Resume KIMMTRAK escalation if the current dose is less than 68 mcg,
or resume at same dose level if dose escalation has completed


Grade 3                   •   Withhold KIMMTRAK until Grade
≤ 1 or baseline.

•   Administer topical corticosteroid and oral corticosteroids
•   For persistent reactions not responding to oral steroids, consider intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent)

•   Resume KIMMTRAK at same dose level (i.e., do not escalate if Grade 3 skin reactions occurred during initial dose escalation; resume escalation once dosage is tolerated)

Grade 4
•   Permanently discontinue
KIMMTRAK
•   Administer intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent) a
Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (NCI CTCAEv4.03).

Special populations

Paediatric population

The safety and efficacy of KIMMTRAK in children under the age of 18 years have not been established. No data are available.

Elderly

No dose adjustment is required for elderly patients (≥ 65 years of age).
Renal impairment

Based on safety and efficacy analyses, dose adjustment is not necessary in patients with mild to moderate renal dysfunction. No dose recommendations can be made for patients with severe renal impairment because of the lack of pharmacokinetic data; therefore, dosing in patients with severe renal impairment should be done with caution and careful monitoring (see section 5.2).

Patients with history of cardiac disease

KIMMTRAK has not been studied in patients with history of significant cardiac disease. Patients with cardiac disease, QT prolongation and risk factors for cardiac failure should be monitored carefully (see section 4.4).

Method of administration

KIMMTRAK is for intravenous use. The recommended infusion period is 15 to 20 minutes.
KIMMTRAK requires dilution with sodium chloride 9 mg/mL (0.9 %) solution for injection containing human albumin for intravenous infusion. Each vial of KIMMTRAK is intended for use as single-dose only. Do not shake the KIMMTRAK vial.

For instructions on dilution and administration of the medicinal product, see section 6.6.

First three treatment doses
First three doses of KIMMTRAK should be administered in a hospital setting with overnight monitoring for signs and symptoms of CRS for at least 16 hours. Vital signs should be monitored pre dose and at a minimum of every 4 hours until resolution of symptoms. If clinically indicated, more frequent monitoring or prolongation of hospitalization should be performed.

If patients experience Grade 3 or 4 hypotension during any of the first three KIMMTRAK infusions, patients should be monitored every hour for at least 4 hours in an outpatient setting for the next three infusions.

If patients experience Grade 2 hypotension during any of the first three KIMMTRAK infusions that last longer than 3 hours, patients should be monitored every hour for at least 4 hours in an outpatient setting for the next three infusions.

Subsequent treatment doses

After 68 mcg dose level is tolerated (i.e., absence of Grade ≥ 2 hypotension requiring medical intervention), subsequent doses can be administered in appropriate outpatient ambulatory care setting.
Patients should be observed for a minimum of 60 minutes following each infusion. For patients who have received outpatient treatment with KIMMTRAK for at least 3 months and have not experienced any interruptions greater than 2 weeks, outpatient monitoring following infusion may be decreased to a minimum of 30 minutes for subsequent doses.