Active Ingredient: Durvalumab
Durvalumab in combination with gemcitabine and cisplatin is indicated for the first-line treatment of adults with unresectable or metastatic biliary tract cancer (BTC).
For this indication, competent medicine agencies globally authorize below treatments:
For:
Regimen A: In case that patient weight is ≥ 36 kg, intravenous, 1,500 milligrams durvalumab, once every 3 weeks. This step is repeated 8 times. Afterwards, in case that patient weight is ≥ 36 kg, intravenous, 1,500 milligrams durvalumab, once every 4 weeks.
Regimen B: In case that patient weight is ≤ 36 kg, intravenous, 20 milligrams durvalumab per kilogram of body weight, once every 3 weeks. This step is repeated 8 times. Afterwards, in case that patient weight is ≤ 36 kg, intravenous, 20 milligrams durvalumab per kilogram of body weight, once every 4 weeks.
Recommended dose: 1,500 mg in combination with chemotherapy every 3 weeks (21 days) up to 8 cycles, followed by 1 500 mg every 4 weeks as monotherapy.
BTC patients with a body weight of 36 kg or less must receive weight-based dosing of durvalumab at 20 mg/kg. In combination with chemotherapy dose every 3 weeks (21 days), followed by 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 36 kg.
Duration of therapy: Until disease progression or until unacceptable toxicity.
Dose escalation or reduction is not recommended. Treatment withholding or discontinuation may be required based on individual safety and tolerability, see the table below.
Guidelines for management of immune-mediated and non-immune-mediated adverse reactions are described in the following table.
Treatment modifications for durvalumab or durvalumab in combination with other products:
| Adverse reactions | Severitya | Treatment modification |
|---|---|---|
| Immune-mediated adverse reactions | ||
| Immune-mediated pneumonitis/interstitial lung disease | Grade 2 | Withhold dose |
| Grade 3 or 4 | Permanently discontinue | |
| Immune-mediated hepatitis | ALT or AST > 3 - ≤ 5 x ULN or total bilirubin > 1.5 - ≤ 3 x ULN | Withhold dose |
| ALT or AST > 5 - ≤ 10 x ULN | Withhold durvalumab and permanently discontinue tremelimumab (where appropriate) | |
| Concurrent ALT or AST > 3 x ULN and total bilirubin > 2 x ULNb | Permanently discontinue | |
| ALT or AST > 10 x ULN or total bilirubin > 3 x ULN | ||
| Immune-mediated hepatitis in HCC (or secondary tumour involvement of the liver with abnormal baseline values)c | ALT or AST > 2.5 - ≤ 5 x BLV and ≤ 20 x ULN | Withhold dose |
| ALT or AST > 5 – 7 x BLV and ≤ 20 x ULN or concurrent ALT or AST 2.5 – 5 x BLV and ≤ 20 x ULN and total bilirubin > 1.5 - < 2 x ULNb | Withhold durvalumab and permanently discontinue tremelimumab (where appropriate). | |
| ALT or AST > 7 x BLV or > 20 ULN whichever occurs first or bilirubin > 3 X ULN | Permanently discontinue | |
| Immune-mediated colitis or diarrhoea | Grade 2 | Withhold dose |
| Grade 3 for durvalumab monotherapy | Withhold dose | |
| Grade 3 for durvalumab + tremelimumab | Permanently discontinue tremelimumabe | |
| Grade 4 | Permanently discontinue | |
| Intestinal perforationd | Any grade | Permanently discontinue |
| Immune-mediated hyperthyroidism, thyroiditis | Grade 2-4 | Withhold dose until clinically stable |
| Immune-mediated hypothyroidism | Grade 2-4 | No changes |
| Immune-mediated adrenal insufficiency or hypophysitis/hypopituitarism | Grade 2-4 | Withhold dose until clinically stable |
| Immune-mediated type 1 diabetes mellitus | Grade 2-4 | No changes |
| Immune-mediated nephritis | Grade 2 with serum creatinine > 1.5 – 3 x (ULN or baseline) | Withhold dose |
| Grade 3 with serum creatinine > 3 x baseline or > 3-6 x ULN; Grade 4 with serum creatinine > 6 x ULN | Permanently discontinue | |
| Immune-mediated rash or dermatitis (including pemphigoid) | Grade 2 for > 1 week | Withhold dose |
| Grade 3 | ||
| Grade 4 | Permanently discontinue | |
| Immune-mediated myocarditis | Grade 2-4 | Permanently discontinue |
| Immune-mediated myositis/polymyositis | Grade 2 or 3 | Withhold dosef |
| Grade 4 | Permanently discontinue | |
| Infusion-related reactions | Grade 1 or 2 | Interrupt or slow the rate of infusion |
| Grade 3 or 4 | Permanently discontinue | |
| Infection | Grade 3 or 4 | Withhold dose until clinically stable |
| Immune-mediated myasthenia gravis | Grade 2-4 | Permanently discontinue |
| Immune-mediated Myelitis transverse | Any grade | Permanently discontinue |
| Immune-mediated meningitis | Grade 2 | Withhold dose |
| Grade 3 or 4 | Permanently discontinue | |
| Immune-mediated encephalitis | Grade 2-4 | Permanently discontinue |
| Immune-mediated Guillain- Barré syndrome | Grade 2-4 | Permanently discontinue |
| Other immune-mediated adverse reactionsh | Grade 2 or 3 | Withhold dose |
| Grade 4 | Permanently discontinue | |
| Non-immune-mediated adverse reactions | ||
| Pure red cell aplasia (PRCA)i | Any Grade | Permanently discontinue |
| Other non-immune-mediated adverse reactions | Grade 2 and 3 | Withhold dose until ≤ Grade 1 or return to baseline |
| Grade 4 | Permanently discontinueg | |
a Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal; BLV: baseline value.
b For patients with alternative cause follow the recommendations for AST or ALT increases without concurrent bilirubin elevations.
c If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.
d Adverse drug reaction is only associated with durvalumab in combination with tremelimumab.
e Permanently discontinue trememlimumab for Grade 3; however, treatment with durvalumab can be resumed once event has resolved.
f Permanently discontinue durvalumab if adverse reaction does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory insufficiency.
g With the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue should be based on accompanying clinical signs/symptoms and clinical judgment.
h Includes immune thrombocytopenia, pancreatitis, immune-mediated arthritis, uveitis and cystitis noninfective.
i Adverse drug reaction is only associated when olaparib maintenance treatment is used in combination with durvalumab, following treatment with durvalumab in combination with platinum-based chemotherapy.
Based on the severity of the adverse reaction, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. After withhold, durvalumab and/or tremelimumab can be resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤10 mg prednisone or equivalent per day. Durvalumab and tremelimumab should be permanently discontinued for recurrent Grade 3 (severe) immune-mediated adverse reactions and for any Grade 4 (life-threatening) immune-mediated adverse reactions, except for endocrinopathies that are controlled with replacement hormones.
It is to be administered as an intravenous infusion solution over 1 hour.
Administer durvalumab prior to chemotherapy on the same day.
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