This regimen has low emetogenic potential refer to local protocol None required routinely. Baseline results valid for 7 days. Results valid for 72 hrs

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1 Regimen : Ipilimumab for Advanced Melanoma ICD10 code Codes pre-fixed with C43. Indication Regimen detail Ipilimumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in people who have received prior therapy, only if the manufacturer provides ipilimumab with the discount agreed in the patient access scheme. Day Drug Dose Route 1 Ipilimumab 3mg/kg Intravenous Administration Ipilimumab may be administered intravenously without dilution or may be diluted in sodium chloride 0.9% or glucose 5% to concentrations of between 1 and 4 mg/ml. Ipilimumab should be administered over 90 minutes using an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 µm to 1.2 µm). Frequency Every 21 days for a total of 4 cycles. Patients should receive all 4 doses as 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. Extravasation Ipilimumab is neutral (Group 1) Premedication Emetogenicity Additional recommended supportive medication Pre-treatment evaluation Regular investigations Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant None required This regimen has low emetogenic potential refer to local protocol None required routinely FBC U+E LFT TSH and free T4 FBC U+E LFT TSH and free T4 Neutrophil count >1.0 x 10 9 /L Platelet count >75 x 10 9 /L Creatinine clearance Bilirubin ALT/AST Alk Phos >30mL/min <3 x ULN <5 x ULN <5 x ULN Inform consultant if there has been an increase in LFT from previous Dose modifications Haematological toxicity WBC <2.0 x 10 9 /L Neutrophils < 1.0 x 10 9 /L Platelets < 75 x 10 9 / L Discuss with the consultant as dose delays are not recommended. The dose should Controlled document Document Number Version Number Page 1 of 5

2 be omitted if appropriate Renal impairment Hepatic 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 Ipilimumab dose 30ml/min Discuss with the consultant See table 1A and 1B in adverse effects section below for when Ipilimumab should be omitted or permanently discontinued. Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Immune-related adverse reactions can be severe or life-threatening and may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. While most immune-related adverse reactions occurred during the induction period, onset months after the last dose of Ipilimumab has also been reported. 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. specific management guidelines for immune-related adverse reactions are described in full in section 4.4 of the Summary of product characteristics available at ncentrate+for+solution+for+infusion/ Management of immune-related adverse reactions may require omission of a dose or permanent discontinuation of Ipilimumab and institution of systemic highdose 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. 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 (see section 4.4 for detailed management guidelines). Severe or life-threatening adverse reactions NCI-CTCAE v3 Grade Gastrointestinal: Severe symptoms (abdominal pain, severe diarrhoea or significant change in the number of stools, blood in stool, gastrointestinal haemorrhage, gastrointestinal perforation) Grade 3 or 4 diarrhoea or colitis Hepatic: Controlled document Document Number Version Number Page 2 of 5

3 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 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 Neurologic: New onset or worsening severe motor or sensory neuropathy Grade 3 or 4 motor or sensory neuropathy Other organ systems: (e.g. nephritis, pneumonitis, pancreatitis, non-infectious myocarditis) Grade 3 immune-related events Grade 2 for immune-related eye disoders NOT responding to topical immunosuppressive therapy Table 1B When to omit scheduled dose of Ipilimumab Omit Ipilimumab dose in patients with the following immune-related adverse reactions. See section 4.4 for detailed management guidelines. Mild to moderate adverse reactions Gastrointestinal: Moderate diarrhoea or colitis that either is not controlled with medical management or that persists (5-7 days) or recurs Hepatic: Moderate elevations in transaminase (AST or ALT > 5 to 8 x ULN) or total bilirubin (> 3 to 5 x ULN) levels Skin: Moderae to severe (Grade 3) skin rash or widespread/intense pruritus regardless of etiology 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. 4. Discontinue Ipilimumab if resolution to Grade 1 or Grade 0 or return to baseline does not occur. Endocrine: Controlled document Document Number Version Number Page 3 of 5

4 Severe adverse reactions in the endocrine glands, such as hypophysitis and thyroiditis that are not adequately controlled with hormone replacement therapy or highdose immunosuppressive therapy Neurological: Moderate (Grade 2) unexplained motor neuropathy, muscle weakness, or sensory neuropathy (lasting more than 4 days) Other moderate adverse reactions Adverse effects Rare or serious side effects Colitis Hepatitis peripheral neuropathy hypopituitarism (including hypophysitis), hypothyroidism Uveitis Glomerulonephritis Frequently occurring side effects Fatigue Diarrhoea Rash pruritis Nausea and vomiting Decreased appetite Abdominal pain Significant drug interactions Comments Cumulative Doses References 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 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. N/A 1. Hodi FS, O'Day SJ, McDermott DF et al Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 2010 Aug 19;363(8): Epub 2010 Jun 5 2. Summary of Product Characteristics Yervoy Accessed on Available at +ml+concentrate+for+solution+for+infusion/ 3. Bristol Myers Squibb Prescribing information Common Toxicity Criteria for Adverse Events Version 4.0, 2009, U.S. Department of Health and Human Services, National Institutes of Health & National Cancer Institute _QuickReference_5x7.pdf 5. South East London Cancer Network. Ipilimumab in melanoma protocol. Controlled document Document Number Version Number Page 4 of 5

5 Accessed Available at 6. NICE technology appraisal 268 Melanoma (stage III or IV) ipilimumab Accessed on Available on Document title Ipilimumab for Malignant Melanoma Document number ASWCS12SKIN004 Approval date 13/02/2013 Written by Anna Kuchel, SpR, BHOC Checked by Georgina Holmes, Pharmacist, Authorised by Review date 13/02/2015 Document reviewed by Version number Summary of changes Version 1 UHBristolNHSFT Jeremy Braybrooke, Chair, ASWCS Network Chemotherapy Group Controlled document Document Number Version Number Page 5 of 5