Ipilimumab in Melanoma Indication: Advanced (unresectable or metastatic) melanoma in adults who have received prior therapy LCNDG criteria to be met: Histologically confirmed unresectable stage III or IV melanoma Previous systemic therapy for metastatic disease containing one or more of the following: dacarbazine, temozolomide, carboplatin, IL-2, interferon or clinical trial of systemic anticancer therapy ECOG PS 1 Treatment plan recommended at a specialist MDT Avoid treatment with Ipilimumab in patients who have an existing autoimmune disease, or who are receiving immunosuppressive therapy. An interval of at least 28 days since treatment with chemotherapy, biochemotherapy, surgery, radiation, or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment is recommended. Regimen details: Ipilimumab 3mg/kg IV 3 weekly Administration: Ipilimumab as an IV infusion over 90 minutes. Can be given intravenously without dilution, or diluted in Sodium chloride 0.9% or Glucose 5% to a concentration between 1 4 mg/ml. Flush the line with Sodium chloride 0.9% or Glucose 5% at the end of the infusion. Frequency: Extravasation: Anti- emetics: Every 21 days, for 4 doses. Entire course of 4 doses should be given if tolerated, regardless of the appearance of new lesions or growth of existing lesions. Assessments of tumour response should be conducted only after completion of induction therapy. Non-vesicant Minimal emetogenicity. Follow Local Anti-emetic Policy Regular investigations: FBC U&E s, LFTs TSH & free T4 Monitor for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy during and before every treatment.(refer to monitoring of immune-related adverse effects, below) Page 1 of 5
Toxicities: Comments: Immune related adverse reactions (gastro-intestinal, hepatic, skin, neurological, endocrinology) including most commonly diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, abdominal pain. Each millilitre of concentrate contains 0.1mmol sodium, which is 2.30mg sodium. To be taken into consideration with controlled sodium diet. Adequate contraception methods should be applied during therapy, and for up 8 weeks after completing the treatment. Infusion related adverse events Discontinue Ipilimumab in severe infusion related reaction, and treat appropriately. Ipilimumab may be administered with close monitoring in mild or moderate infusion related reactions. Consider pre-medication with antipyretic (paracetamol) and antihistamine (chlorphenamine). Full resuscitation facilities and an anaphylaxis kit must be available at all times. Immune-related adverse reactions Immune related adverse reactions can be severe or life-threatening. They may involve the gastro-intestinal, liver, skin, nervous, endocrine or other organ systems. Rarely the onset of these has been reported months after the last administered Ipilimumab dose. Unless an alternate etiology has been identified, diarrhoea, increased stool frequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatory and Ipilimumab related. Early diagnosis and appropriate management are essential to minimise life-threatening complications. Systemic high-dose corticosteroid with or without additional immunosuppressive therapy may be required for management of severe immune related adverse reactions. Refer to full Summary of product characteristics (www.medicines.org.uk/emc/) for symptom specific management guidelines in treating immune related toxicities. DOSE MODIFICATIONS Management of immune-related adverse reactions may require omission of a dose or permanent discontinuation of Ipilimumab and institution of systemic high-dose corticosteroid or, in some cases, the addition of other immunosuppressive therapy (See tables 1A and 1B below). Dose reduction is not recommended. Doses that are omitted due to an adverse reaction must not be replaced. Refer to full Summary of product characteristics (www.medicines.org.uk/emc/) for symptom specific management guidelines in treating immune related toxicities. Page 2 of 5
Table 1A When to permanently discontinue Ipilimumab Permanently discontinue Ipilimumab in patients with the following adverse reactions. Management of these adverse reactions may also require systemic high-dose corticosteroid therapy if demonstrated or suspected to be immune-related Severe or life-threatening adverse reactions Gastrointestinal: Severe symptoms (abdominal pain, severe diarrhoea or significant change in the number of stools, blood in stool, gastrointestinal haemorrhage, gastrointestinal perforation). NCI-CTCAE v3 Grade a Grade 3 or 4 diarrhoea or colitis Consider initiating Methylprednisolone 2mg/kg/day, tapering slowly once symptoms are controlled. Evaluate for evidence of gastrointestinal perforation or peritonitis. Hepatic: Severe elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin or symptoms of hepatotoxicity. AST or ALT > 8 x ULN or Total bilirubin > 5 x ULN Initiate methylprednisolone 2mg/kg/daily, tapering slowly (over at least one month) once elevations are normalized. Skin: Life threatening skin rash (including Stevens-Johnson syndrome or toxic epidermal necrolysis) or severe widespread pruritus interfering with activities of daily living or requiring medical intervention. Grade 4 rash or Grade 3 pruritus Initiate systemic IV methylprednisolone 2mg/kg/day, tapering slowly (over at least one month) once rash or pruritus is controlled. Neurologic: New onset or worsening severe motor or sensory neuropathy. Grade 3 or 4 motor or sensory neuropathy Initiate IV methylprednisolone 2mg/kg/day. Other organ systems b : (e.g. nephritis, pneumonitis, pancreatitis, noninfectious myocarditis) Consider immediate high-dose corticosteroid therapy as per local treatment guidelines. Grade 3 immune-related events c Grade 2 for immune-related eye disorders NOT responding to topical immunosuppressive therapy a Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3). b Any other adverse reactions that are demonstrated or suspected to be immune-related should be graded according to CTCAE. Decision whether to discontinue Ipilimumab should be based on severity. c Patients with severe (Grade 3 or 4) endocrinopathy controlled with hormone replacement therapy may remain on therapy. ULN = upper limit of normal Page 3 of 5
Table 1B When to omit scheduled dose of Ipilimumab Omit Ipilimumab dose a in patients with the following immune-related adverse reactions. Mild to moderate adverse reactions Gastrointestinal: Moderate diarrhoea or colitis that either is not controlled with medical management (loperamide, fluid replacement) or that persists (5-7 days) or recurs (consider prednisolone 1mg/kg PO once daily) Hepatic: Moderate elevations in transaminase (AST or ALT > 5 to ULN) or total bilirubin (> 3 to 5 x ULN) levels Skin: Moderate to severe (Grade 3) b skin rash or widespread/intense pruritus regardless of etiology. Add antihistamine therapy to control symptoms, treat rash with topical and oral corticosteroids (prednisolone 1mg/kg PO once daily). Endocrine: Severe adverse reactions in the endocrine glands, such as hypophysitis and thyroiditis that are not adequately controlled with hormone replacement therapy or high-dose immunosuppressive therapy. 8 x Action 1. Omit dose until an adverse reaction resolves to Grade 1 or Grade 0 (or returns to baseline). 2. If resolution occurs before the next scheduled dose, resume therapy at next scheduled dose. 3. If resolution has not occurred before next scheduled dose, continue to omit doses until resolution then resume treatment schedule. Do not re-place omitted doses. 4. Discontinue Ipilimumab if resolution to Grade 1 or Grade 0 or return to baseline does not occur. If pituitary imaging or lab tests are abnormal, consider a short course of dexamethasone 4mg 6-hourly to treat the inflammation of the gland, tapering slowly (over at least one month) once symptoms improved. Long-term hormone replacement therapy may be necessary. Neurological: Moderate (Grade 2) b unexplained motor neuropathy, muscle weakness, or sensory neuropathy (lasting more than 4 days) Other moderate adverse reactions c (uveitis, easinophilia, lipase elevation, glomerulonephritis, iritis, haemolytic anaemia, amylase elevations, multi-organ failure, pneumonitis have been reported) Treat Ipilimumab related uveitis, iritis or episcleritis with topical corticosteroid eye-drops. a No dose reduction of Ipilimumab is recommended. Doses that are omitted due to an adverse reaction must not be replaced. b Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3). c Any other organ system adverse reactions that are considered immune-related should be graded according to CTCAE. Decision whether to omit a scheduled dose should be based on severity. ULN = upper limit of normal Page 4 of 5
Haematological Toxicity WBC <2.0 x 10 9 /L or Neutrophils < 1.0 x 10 9 /L or Platelets < 75 x 10 9 / L Discuss with the consultant Dose delays are not recommended, omit the dose if appropriate Renal impairment: The safety and efficacy have not been studied in patients with renal impairment. No specific dose adjustment is recommended in mild to moderate renal function. CrCl 30ml/min Ipilimumab dose Discuss with the consultant Hepatic impairment: The safety and efficacy have not been studied in patients with hepatic impairment. Administer with caution if transaminases 5 x ULN or bilirubin > 3 x ULN at baseline. Increases in AST and ALT or total bilirubin should be evaluated to exclude causes of hepatic injury, including infections, disease progression or medicinal products. Liver biopsies from patients with immune-related hepatotoxicity have shown evidence of acute infection (neutrophils, lymphocytes, macrophages). Drug interactions: Baseline systemic corticosteroids, initiated before starting Ipilimumab, should be avoided. Anticoagulants- increased risk of GI haemorrhage, monitor closely. Vaccinations should not be administered for 4 weeks before and after Ipilimumab. References: www.medicines.org.uk Micromedex review: Ipilimumab, accessed Sept-11 Bristol-Myers Squibb Expanded Access Programme for ipilimumab UK version of 09 July2010 Page 5 of 5