CAPIRI (XELIRI or Irinotecan & Capecitabine) DRUG ADMINISTRATION SCHEDULE Day Drug Dose Route Diluent &Rate Glucose 5% 500ml Infusion Fast Running / Line Flush Ondansetron 8mg Oral /Slow bolus/15 min infusion Day 1 Dexamethasone 8mg IV bolus Via Glucose drip 250ml Glucose 5% Irinotecan 200mg/m2 IV Infusion over 2 hours Days 1 800 mg/m2 Capecitabine Oral N/A to 14 twice a day *Ondansetron IV must be infused over 15 minutes in patients over 65 years of age.

PREMEDICATION *If acute cholinergic syndrome appears atropine sulphate 250micrograms should be administered by subcutaneous injection unless clinically contraindicated. The manufacturer recommends the use of prophylactic atropine sulphate with subsequent doses of irinotecan.

DOSE FORM Capecitabine available as 500mg and 150mg tablets.

CYCLE LENGTH AND NUMBER OF DAYS Treatment administered every 21 days, usually for up to 8 cycles.

APPROVED INDICATIONS Treatment of Advanced Colorectal Cancer, in patients who would otherwise be considered for Irinotecan-MdG (FOLFIRI).

ELIGIABILITY CRITERIA Colorectal cancer patients with adequate renal function.

EXCLUSION CRITERIA  Patients with baseline renal function less than 30 ml/min.  Patients incapable of managing oral chemotherapy themselves or with the assistance of a carer  Patients with swallowing difficulties

RECOMMENDED TAKE HOME MEDICATION Ondansetron 8mg twice daily for 2 days Dexamethasone 4mg twice daily for 1 day Metoclopramide 10mg three times daily as required Loperamide as required (4mg after first loose stool and 2mgs every 2 hours, to a maximum of 16 (2mg) tablets in 24 hours. For diarrhoea lasting greater than 24 hours give ciprofloxacin 250mg BD.

INVESTIGATIONS / MONITORING REQUIRED FBC, U&E’s, LFT’s & tumour markers as appropriate prior to each course of chemotherapy FBC on the day of chemotherapy Where CEA is elevated this should be measured before each cycle.

CAPIRI (Capecitabine Irinotecan) CRP09 CR017 V1.4 Page 1 of 5 Issue Date 28.02.18 Expiry Date: 01.03.2021 CAPIRI (XELIRI or Irinotecan & Capecitabine) ASSESSMENT OF RESPONSE Assessed radiologically after 4th cycle. 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  Irinotecan must only be given in units where clear arrangements are made to manage possible toxicity related out of hour's admissions. Patients must be made aware of the risk of delayed diarrhoea occurring 24 hours after the administration of Irinotecan and at any time before the next cycle. This means supplying information sheets to the patient and if appropriate to their GP.  Early onset diarrhoea (within the first 24 hours). Can be a result of acute cholinergic syndrome and may occur in 9% of patients. Symptoms are short lasting and respond within minutes to administration of atropine (0.25-1mg subcutaneously)  Delayed diarrhoea must be treated immediately with high dose Loperamide (4mg after first loose stool and 2mgs every 2 hours, to a maximum of 16 (2mg) tablets in 24 hours. Hospitalise if condition not resolved in 48 hours.  Capecitabine should start on the evening of day 1 and continue until the morning of day 15.  Capecitabine should be omitted if Grade II toxicity occurs. It can recommence (see Dose Reductions) if toxicity resolves, however the treatment should still stop on day 15. (i.e. Doses are omitted not delayed).  Note: Grade II Toxicity includes: Diarrhoea defined as an increase of 4-6 stools per day or nocturnal stools.

TOXICITIES  Acute cholinergic syndrome (defined as early diarrhoea and various other symptoms such as sweating, abdominal cramping, lacrimation, myosis and salivation)  Diarrhoea –risk of severe delayed diarrhoea – can be life threatening  Nausea and Vomiting  Stomatitis  Palmar/Plantar Erythrodysesthesia (PPE) - Can be severe, patients must be forewarned  Pyrexia, fatigue, asthenia, anorexia  Myelosuppression  Hyperbilirubinemia  Cardiotoxicity - Occasionally patients may experience coronary artery spasm. Stop Treatment with fluoropyrimidine therapy if this occurs.

CAPIRI (Capecitabine Irinotecan) CRP09 CR017 V1.4 Page 2 of 5 Issue Date 28.02.18 Expiry Date: 01.03.2021 CAPIRI (XELIRI or Irinotecan & Capecitabine) DPD Deficiency and Severe Toxicity Risk Dihydropyrimidine dehydrogenase (DPD) plays an important role in the metabolism of fluoropyrimidine drugs 5-fluorouracil (5FU) and capecitabine. Patients with DPD deficiency may be predisposed to experience increased or severe toxicity when receiving 5-FU or capecitabine, and in some cases these events can be fatal. For all patients having capecitabine or fluorouracil, the risk of severe side effects from capecitabine or 5FU if patients have a deficiency of DPD must be mentioned and patient given a copy of the DPD toxicity information leaflet from cancer research UK. Available At http://www.cancerresearchuk.org/about-cancer/cancer-in- general/treatment/chemotherapy/side-effects/dpd-deficiency-and-fluorouracil

EXTRAVASATION See NCA / local Policy

DOSE MODIFICATION / TREATMENT DELAYS Haematological toxicity:  Discuss with consultant if ANC 1 to 1.5 and/ or Platelets < 75 to 100.  Delay 1 week if ANC < 1 and/or PLTs < 75.  No dose reduction for CTC grade I/II ANC  Grade III/IV ANC → delay chemotherapy until recovered, then proceed at 20% capecitabine and Irinotecan dose reduction  If further delay(s) for bone marrow suppression occur despite a 20% dose reduction, consider a further 20% dose reduction.

Non-haematological toxicity: Diarrhoea Grade 1 (watery stool 2-3 times/day) Loperamide 4mg then 2mg QDS PRN. Grade 2 (watery stool 4-6 times/day) Delay treatment until recovered and give full dose Grade 3/4 (watery stool >7 times/day) Delay until recovered and resume treatment at 25% reduced dose of oxaliplatin and irinotecan

Table of dose adjustments according to CTC toxicity (Not PPE/hand/foot syndrome) Grade 2 Grade 3 Grade 4 Interrupt treatment until Interrupt treatment until resolved to grade 0/1, then resolved to grade 0/1, then Discontinue 1st appearance continue at 100% of original continue at 75% of original treatment dose with prophylaxis where dose with prophylaxis possible where possible Interrupt treatment until Interrupt treatment until resolved to grade 0/1, then resolved to grade 0/1, then 2nd appearance continue at 75% of original continue at 50% of original dose dose Interrupt treatment until resolved to grade 0/1, then 3rd appearance Discontinue treatment continue at 50% of original dose 4th appearance Discontinue treatment

CAPIRI (Capecitabine Irinotecan) CRP09 CR017 V1.4 Page 3 of 5 Issue Date 28.02.18 Expiry Date: 01.03.2021 CAPIRI (XELIRI or Irinotecan & Capecitabine) Once the capecitabine dose has been reduced, it should not be increased at a later time. Omitted doses are not replaced or restored, instead the patient should resume the planned treatment cycle.

Table of PPE (hand/foot syndrome) toxicity grading for capecitabine only Grade Clinical Functional Management Numbness, Discomfort but no interruption 1 dysesthesia/parathesi of normal activities Painfula, tingling, erythema painless with Discomfort which affects Interrupt treatment 2 swelling or erythema activities of daily living until grade ≤1 Moist desquamation, Severe discomfort, unable to Interrupt treatment 3 ulceration, Blistering, work or perform activities of until grade ≤1 and severe pain daily living reduce dose by 25%

Once the capecitabine dose has been reduced, it should not be increased at a later time. Omitted doses are not replaced or restored, instead the patient should resume the planned treatment cycle.

Hepatic impairment Administration of capecitabine should be interrupted if treatment-related elevations in bilirubin of > 3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of > 2.5 x ULN occur. Treatment with capecitabine monotherapy may be resumed when bilirubin decreases to ≤ 3.0 x ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN.

Renal function GFR Capecitabine Oxaliplatin 30-50 ml/min 25% dose reduction No action < 30 ml/min Contact prescriber Contact prescriber

REFERENCES: 1. Reinacher-Schick AC et al. Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): a randomized phase II study of the AIO Colorecal Study Group (AIO trial 0604). Am Soc Clin Oncol 2008; Abstract 4030 2. Koopman M et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007; 370: 135-42 3. Ducreux M et al. Efficacy and safety of bevacizumab (BEV)-based combination regimens in patients with metastatic colorectal cancer (mCRC): Randomised phase II study of BEV + FOLFIRI versus BEV + XELIRI (FNCLCC ACCORD13/0503 study). Am Soc Clin Oncol, Annual Meeting 2009; Abstract 4086 and associated oral presentation

CAPIRI (Capecitabine Irinotecan) CRP09 CR017 V1.4 Page 4 of 5 Issue Date 28.02.18 Expiry Date: 01.03.2021 CAPIRI (XELIRI or Irinotecan & Capecitabine) Document Control Document Title: CAPIRI-XELIRI CNTW protocol CRP09 CR017 Current Document No: CRP09 CR017 1.4 Version: Chris Beck Chemotherapy Pharmacist Date Reviewer: 28.02.18 Northern Cancer Alliance Approved: Steve Williamson Consultant Due for Approved by: 01.03.21 Pharmacist Northern Cancer Alliance Review Summary of 1.1 Amended inconsistencies in dose adjustment advice, updated toxicities list. Changes 1.2 Protocol reviewed. Volume of Irinotecan infusion amended.

1.3 Protocol reviewed and reissued, Antiemetic advice updated

1.4 Protocol reviewed, parameters updated from Chemocare. DPD toxicity advice added

CAPIRI (Capecitabine Irinotecan) CRP09 CR017 V1.4 Page 5 of 5 Issue Date 28.02.18 Expiry Date: 01.03.2021