NECN CHEMOTHERAPY HANDBOOK PROTOCOL

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1 Nivolumab (Opdivo ) for treatment of advanced melanoma and Renal Cell Cancer (Also advanced/ metastatic NSCLC EMAS patients only -Nov 2016) DRUG ADMINISTRATION SCHEDULE (SINGLE AGENT Day Drug Daily dose Route Diluent Rate 1 Nivolumab* 3mg/kg IV infusion Sodium chloride 0.9% 100mL 60 minutes Cycle Length and Number of Days Every 14 days until disease progression or unacceptable toxicity. DRUG ADMINISTRATION SCHEDULE (COMBINATION) When given in combination with iplilumimab for malignant melanoma an alternative lower dose schedule (1mg/kg) is used for first 4 cycles of a 21 day cycle. Day Drug Daily dose Route Diluent Rate 1 Nivolumab* 1mg/kg IV infusion 100mL Sodium chloride 0.9% 60 minutes 1 Iplilumimab 3 mg/kg IV Infusion 100 ml Sodium chloride 0.9% 90 minutes Cycle Length and Number of Days Every 21 days for 4 cycles then stop iplilumimab and continue on 2 weekly nivolumab at 3mg/kg as above Nivolumab is supplied as 40mg or 100mg single-use vials, each containing 10mL or 40mL, respectively. It must be prepared in pharmacy aseptic units and treated with the same precautions as cytotoxic medicines. APPROVED INDICATIONS Nivolumab for monotherapy or in combination with iplilumimab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. Nivolumab for second and subsequent line treatment of renal cell cancer is available on Cancer Drug Fund following Draft NICE approval on (Note funding will transfer from CDF to baseline commissioning 30 days after final NICE TA issued) Nivolumab for second line treatment of non-small cell lung cancer is only available under the EAMS scheme for patients in nivolumab for melanoma and rcc s Page 1 of 5

2 PREMEDICATION Not routinely required. RECOMMENDED TAKE HOME MEDICATION Metoclopramide 10mg TDS as required. INVESTIGATIONS / MONITORING REQUIRED PD-L1 test (non-squamous NSCLC only). FBC, U&E, LFT, including glucose and bicarbonate at baseline and before each dose. ASSESSMENT OF RESPONSE Metastatic: Tumour size and patient symptomatic response. REVIEW BY CLINICIAN To be reviewed by either a Nurse, Pharmacist or Clinician before every cycle. NURSE / PHARMACIST LED REVIEW On cycles where not seen by clinician. ADMINISTRATION NOTES CAUTION Nivolumab administration can result in severe and fatal immune-mediated adverse reactions (iraes). iraes may involve gastrointestinal, endocrine, skin, liver, nervous, lung and other organ systems. Unless an alternate aetiology has been identified, signs and symptoms suggestive of iraes must be considered inflammatory and Immunotherapy 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 iraes Patients should be monitored continuously (at least up to 5 months after the last dose) mas an adverse reaction with Nivolumab may occur at any time during or after discontinuation of Nivolumab therapy. Nivolumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy. Nivolumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction. Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 µm to 1.2 µm) Patients should be given an alert card and be told to report any side effects EXTRAVASATION See NECN/Local Policy nivolumab for melanoma and rcc s Page 2 of 5

3 TOXICITIES (None Immune related) Fatigue Pruritis and rash Diarrhoea Nausea Muscle pain Respiratory tract infections LFT derangement Reduced appetite Peripheral neuropathy DOSE MODIFICATION / TREATMENT DELAYS adverse reaction pneumonitis Severity Grade 2 Treatment modification Withhold nivolumab until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete. Initiate corticosteroids at a dose of 1mg/kg/day May resume nivolumab after corticosteroid taper. If there is no improvement, increase dose to 2 to 4mg/kg/day methylprednisolone IV or oral equivalent and permanently discontinue nivolumab colitis Grade 3 or 4 Grade 2 or 3 Permanently discontinue nivolumab. Initiate corticosteroids at a dose of 2 to 4mg/kg/day methylprednisolone IV or oral equivalent Withhold nivolumab until symptoms resolve. Grade 2 if persistent, manage with corticosteroids at a dose of 0.5 to 1mg/kg/day Upon improvement, taper corticosteroid and resume nivolumab. If worsening or no improvement, increase corticosteroid dose to 1 to 2 mg/kg/day methylprednisolone IV or oral equivalent and Grade 3 Initiate corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone IV or oral equivalent. Upon improvement, taper corticosteroid and resume nivolumab. If worsening or no improvement, permanently discontinue nivolumab. Permanently discontinue Nivolumab. Initiate nivolumab for melanoma and rcc s Page 3 of 5

4 hepatitis nephritis and renal dysfunction rash Grade 2 elevation is AST, ALT or bilirubin Grade 3 or 4 elevation is AST, ALT or bilirubin Grade 2 or 3 creatinine increase creatinine increase Grade 3 Withhold Nivolumab until values return to baseline, and corticosteroids are complete. If values are persistently high, give corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone IV or oral equivalent. Upon improvement, taper corticosteroid and resume Nivolumab. If worsening or no improvement despite corticosteroids, increase dose to 1 to 2 mg/kg/day methylprednisolone IV or oral equivalent and Permanently discontinue Nivolumab. Initiate Withhold Nivolumab until creatinine returns to baseline. Initiate corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone IV or oral equivalent. Upon improvement, taper corticosteroid and resume Nivolumab. If worsening or no improvement, increase corticosteroids to 1 to 2 mg/kg/day methylprednisolone IV or oral equivalent, and permanently discontinue Nivolumab. Initiate Withhold Nivolumab until symptoms resolve and management with corticosteroids is complete. In severe rash, initiate corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone IV or oral equivalent. If immunosuppression with corticosteroids is used to treat an immune-related rash, a taper of at least 1 month duration should be initiated upon improvement. Manage the same as grade 3, however endocrinopathies Symptomatic grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis Grade 2 adrenal insufficiency Grade 3 diabetes hypothyroidism, hyperthyroidism, hypophysitis, diabetes Grade 3 or 4 adrenal insufficiency. Withhold Nivolumab until symptoms resolve and management with corticosteroids is complete. Permanently discontinue Nivolumab nivolumab for melanoma and rcc s Page 4 of 5

5 Non- Haematological Toxicity: No dose adjustment for mild hepatic impairment. Nivolumab must be administered with caution in patients with moderate (total bilirubin > 1.5 x to 3 x the upper limit of normal [ULN] and any AST) or severe (total bilirubin > 3 x ULN and any AST) hepatic impairment No dose adjustment is required in patients with mild to moderate renal impairment. Data from patients with severe renal impairment are too limited to draw conclusions on this population. TREATMENT LOCATION Can be given at Cancer Centre or Cancer unit REFERENCES Summary of Product Characteristics: Nivolumab (Opdivo ) Accessed 04/11/16. Nivolumab for treating advanced (unresectable or metastatic) melanoma. NICE technology appraisal guidance [TA384] Published date: 18 February 2016 Nivolumab in combination with ipilimumab for treating advanced melanoma. NICE technology appraisal guidance [TA400] Published date: 27 July 2016 Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19): Brahmer J, Reckamp K, BaasP et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. NEJM (2): EXTRAVASATION See NECN/Local Policy Document Control Document Title: Nivolumab for Melanoma and RCC S Document No: CHEMO S Current Version: Authors: Approval Date Summary of Changes Gina Kilvington (pre-registration Pharmacist, Northumbria Approved by: Review Date 1.0 Steve Williamson Consultant Pharmacist, NHS England nivolumab for melanoma and rcc s Page 5 of 5