Docetaxel + Nintedanib Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton community Derby community Burton out-patient Derby out-patient Indication Second line management of non-small cell lung cancer of adenocarcinoma histology Treatment Intent Palliative Anti-Emetics Pre-chemotherapy 3 Post-chemotherapy B Day 0 Dexamethasone 8mg Oral, twice a day, starting 24 hours prior to docetaxel & continued for a total of six doses (3days) Day 1 Docetaxel 75mg/m 2 Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes Day 2 Nintedanib 200mg Oral every 12 hours for 20 days (See notes below) Frequency & duration: every 21 days until disease progression or unacceptable toxicity. Patients may continue with nintedanib monotherapy following at least 4 cycles of docetaxel + nintedanib, after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs. (See separate protocol) Notes: 1. FBC, U&Es and LFTs must be taken prior to Day 1 of each cycle. 2. Docetaxel should be considered where second line treatment is appropriate for patients with locally advanced or metastatic NSCLC when relapse has occurred after prior chemotherapy 3. Nintedanib (Vargatef ) capsules must be taken orally, preferably with food, swallowed whole with water, and must not be chewed or crushed AUTHORISED BY: Dr M Keni & PAGE 1 of 6
4. Nintedanib (Vargatef ) must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses. The recommended maximum daily dose of 400 mg should not be exceeded 5. Docetaxel should be administered when the neutrophil count is 1.5 x 10 9 /L 6. Docetaxel Dose Modifications Haematological o Neutrophils Adverse event 1. Grade 4 neutropenia* for 7 days or more. 2. Grade 3-4 neutropenia with oral fever >38.5 C 3. Infection* (i.e. documented infection with grade 3-4 neutropenia) *according to NCI-CTC version 3 Action If the patient develops one of these adverse events, the next infusion should be given at 60mg/m 2 (i.e. a dose reduction) ANC on Day of Treatment Action 1.5x10 9 /L Treat on time < 1.5 x 10 9 /L Delay maximum 2 weeks Blood counts have to be performed until ANC 1.5 x 10 9 /l. Then treat with a dose reduction. (i.e. 60mg/m 2 ) Further dose modifications are the Consultant s decision If no recovery (ANC still < 1.5 x 10 9 /l) after 2 week delay: stop treatment. o Platelets In case of grade >3 platelets (NCI-CTC), delay maximum 2 weeks until platelets recover to >100 x 10 9 /l, then treat with a dose reduction (i.e. 60mg/m 2 ). IF DOCETAXEL ADMINISTRATION IS DEFERRED, SHOULD CONTINUE - ONLY WITHOLD ON THE DAY OF DOCETAXEL ADMINISTRATION AUTHORISED BY: Dr M Keni & PAGE 2 of 6
Hypersensitivity reactions with Docetaxel (This is rare with premedication, but when it Occurs it is usually within the first few minutes of Infusion in either Cycle 1 or 2.) MILD symptoms Skin rash,flushing or pruritis MODERATE symptoms Generalised pruritis or rash, dyspnoea, mild hypotension SEVERE symptoms Bronchospasm, generalised urticaria, angio-oedema, hypotension (systolic < 80mmHg) Decrease rate of infusion & monitor patient until recovery- then continue as before STOP docetaxel infusion & give IV antihistamine & steroids- resume docetaxel after recovery- for further cycles give IV antihistamine & steroids 1 hour prior to infusion plus usual premedication STOP docetaxel infusion & give IV antihistamine & steroids as above give adrenaline & salbutamol (if wheezing) - IV fluids may be necessary for hypotension N.B. After a severe hypersensitivity reaction the patient must be withdrawn from treatment. Stomatitis Grade 2: No change, study chemotherapy should be withheld until resolution to grade 1. Grade 3: If grade 3 stomatitis occurs, study drug should be withheld until resolution to grade 1. Treatment may then be resumed, but the dose should be reduced to 60mg/m 2 all subsequent doses. Grade 4: In case of grade 4 stomatitis, the patient should stop treatment. Peripheral Neuropathy If symptoms or signs experienced by the patient, dose modification should be performed as follows:- Grade 1: no change Grade 2: reduce dose to 60mg/m 2 Grade 3: stop treatment. Skin Toxicity Grade 2: no change Grade 3: delay until grade 1, maximum two weeks then reduce dose to 60mg/m 2 ; if no recovery to grade 1 within two weeks delay, patient should stop treatment. IF DOCETAXEL ADMINISTRATION IS DEFERRED, SHOULD CONTINUE - ONLY WITHOLD ON THE DAY OF DOCETAXEL ADMINISTRATION AUTHORISED BY: Dr M Keni & PAGE 3 of 6
7. In patients who experienced either febrile neutropenia, neutrophil <0.5 x 10 9 /L for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued. IF DOCETAXEL ADMINISTRATION IS DEFERRED, SHOULD CONTINUE - ONLY WITHOLD ON THE DAY OF DOCETAXEL ADMINISTRATION 8. Alcohol content Docetaxel contains up to 5g (approx. 0.5 unit) of ethanol per maximum dose. Patients should be advised not to drive on the day of treatment. Consider alternative chemotherapy agents for patients where alcohol content is a concern. 9. Nintedanib Dose adjustments As initial measure for the management of adverse reactions (see Tables 1 and 2) treatment with nintedanib should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline). Nintedanib treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in Table 1 and Table 2. In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twice daily, treatment with nintedanib should be permanently discontinued. In case of specific elevations of aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) values to > 3 x upper limit normal (ULN) in conjunction with an increase of total bilirubin to 2 x ULN and alkaline phosphatase (ALKP) < 2 x ULN; (see Table 2) treatment with Vargatef should be interrupted. Unless there is an alternative cause established, Vargatef should be permanently discontinued. AUTHORISED BY: Dr M Keni & PAGE 4 of 6
CTCAE* Adverse reaction Table 1: Recommended dose adjustments for Vargatef (nintedanib) in case of diarrhoea, vomiting and other non-haematological or haematological adverse reactions Diarrhoea grade 2 for more than 7 consecutive days despite anti-diarrhoeal treatment OR Diarrhoea grade 3 despite anti-diarrhoeal treatment Vomiting grade 2 AND/OR Nausea grade 3 despite anti-emetic treatment Dose adjustment Other non-haematological or haematological adverse reaction of grade 3 * CTCAE: Common Terminology Criteria for Adverse Events After treatment interruption and recovery to grade 1 or baseline, dose reduction from 200 mg twice daily to 150 mg twice daily and - if a 2 nd dose reduction is considered necessary - from 150 mg twice daily to 100 mg twice daily. Table 2: Recommended dose adjustments for Vargatef (nintedanib) in case of AST and/or ALT and bilirubin elevations AST / ALT and bilirubin elevations Dose adjustment Elevation of AST and/or ALT values to > 2.5 x ULN in conjunction with total bilirubin elevation to 1.5 x ULN OR Elevation of AST and/or ALT values to > 5x ULN Elevation of AST and/or ALT values to > 3 x ULN in conjunction with an increase of total bilirubin to 2 x ULN and ALKP < 2 x ULN After treatment interruption and recovery of transaminase-values to 2.5 x ULN in conjunction with bilirubin to normal, dose reduction from 200 mg twice daily to 150 mg twice daily and - if a 2 nd dose reduction is considered necessary - from 150 mg twice daily to 100 mg twice daily. Unless there is an alternative cause established, Vargatef should be permanently discontinued AST: Aspartate aminotransferase; ALT: Alanine aminotransferase ALKP: Alkaline phosphatase; ULN: Upper limit normal AUTHORISED BY: Dr M Keni & PAGE 5 of 6
10. Renal impairment Less than 1 % of a single dose of nintedanib is excreted via the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (< 30 ml/min creatinine clearance). 11. Hepatic impairment Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90 %). No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A). The safety, efficacy, and pharmacokinetics of nintedanib have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Therefore, treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with nintedanib is not recommended. References: 1. Boehringer Ingelheim Limited Summary of Product Chracteristics; Vargatef 150 mg soft capsules. Last Updated on emc 18-Mar-2015 (Accessed 10 th September 2015) 2. Nintedanib for previously treated locally advanced, metastatic, or locally recurrent non small cell lung cancer. NICE technology appraisal guidance [TA347] Published date: July 2015 3. Communication with Boehringer Ingelheim, 10 th September 2015. AUTHORISED BY: Dr M Keni & PAGE 6 of 6