DERBY-BURTON LOCAL CANCER NETWORK FILENAME Peruse.DOC CONTROLLED DOC NO: CCPG R29

Transcription

1 Pertuzumab + Trastuzumab + Docetaxel (Peruse study) A Multicenter, open-label, single arm study of Pertuzumab in combination with Trastuzumab and a Taxane in first-line treatment of patients with HER2-positive advanced (metastatic or locally recurrent) breast cancer ***See protocol for further details *** 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 HER-2 +ve Advanced Breast Cancer Treatment Intent Palliative Anti-Emetics Cycle 1 Pre-chemotherapy Day 2 3 Post-chemotherapy Day 2 A Cycle 2 onwards Pre-chemotherapy Day 1 3 Post-chemotherapy Day 1 A Cycle 1 Day 1 Pertuzumab 840mg Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes Followed by Trastuzumab 8mg/kg Intravenous infusion in 250ml sodium chloride 0.9% over 90 minutes Dexamethasone 8mg Oral twice daily, starting 24 hours prior to docetaxel & continued for a total of six doses (3days) Day 2 Docetaxel 75mg/m 2 Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes AUTHORISED BY: Dr P Chakraborti PAGE 1 of 6

2 Cycle 2 onwards Day 0 Dexamethasone 8mg Oral twice daily, starting 24 hours prior to docetaxel & continued for a total of six doses (3days) Day 1 Pertuzumab 420mg Intravenous infusion in 250ml sodium chloride 0.9% over 30 minutes* Followed Trastuzumab 6mg/kg Intravenous infusion in 250ml sodium chloride by Followed by 0.9% over 30 minutes** Docetaxel 75mg/m 2 Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes * If the initial dose of Pertuzumab is not well tolerated in cycle 1, continue to administer subsequent doses over 60 minutes (Ref: Peruse Protocol). ** If the initial dose of Trastuzumab is not well tolerated in cycle 1, continue to administer subsequent doses over 90 minutes (Ref: SPC Herceptin). Frequency & duration: Every 21 days. Docetaxel should be given for 6 cycles, with Pertuzumab and Trastuzumab therapy continuing until predefined study end, unacceptable toxicity, withdrawal of consent or disease progression (see Protocol). Notes: To be used in conjunction with the Protocol 1. FBC, U&Es and LFTs must be taken prior to Day 1 of each cycle. 2. Prior to initial treatment (cycle 1), the following must apply: ANC > 1.5 x 10 9 /l Platelets > 100 x 10 9 /l Hb > 9g/dl SrCr < 177 micromol/l Total bilirubin < ULN (unless patient has Gilberts syndrome) AST < 2.5 x ULN (<5 x ULN in patients with liver metastases) ALP < 2.5 x ULN (<10 x ULN in patients with bone metastases) INR & aptt < 1.5 x ULN (unless on therapeutic anti-coagulation) 3. Pertuzumab, Trastuzumab and Docetaxel can be administered in any order on day 1 or day 2 (see section , and of the Protocol) but for the first cycle at least, it is recommended to administer Pertuzumab on day 1 and Trastuzumab and Docetaxel on day 2. However, on discussion with trial staff & Dr Chakraborti, it is ok to give as scheduled above. 4. In the case of surgery during the study, there is no evidence that the HER2 antibodies delay wound healing, but patients should have recovered from surgery AUTHORISED BY: Dr P Chakraborti PAGE 2 of 6

3 and anesthesia (including liver functions) for a minimum of 14 days before antibody treatment. 5. Pertuzumab and trastuzumab administration may be delayed to assess or treat adverse events such as cardiac adverse events, myelosuppression, or other events. No dose reduction will be allowed for pertuzumab or trastuzumab. - If loading doses for pertuzumab or trastuzumab are incomplete, refer to section of the protocol for guidance. - If a dose of pertuzumab or trastuzumab is delayed, refer to section of the protocol for guidance. In case of delay to the administration of study treatments, the schedule of drug administration will always refer to the first drug to be administered (i.e. pertuzumab). 6. Cardiac safety: All patients must have a baseline > 50% prior to treatment (ECHO or MUGA scan, with ECHO as the preferred method) and should be monitored regularly according to the Schedule of Assessments (Appendix 1 of Protocol). Patients should be reassessed with the same technique throughout the study. If an investigator is concerned that an adverse event (AE) may be related to cardiac dysfunction, an additional measurement should be performed. Pertuzumab, trastuzumab and docetaxel will be discontinued in any patient who develops clinical signs and symptoms suggesting CHF, with the diagnosis confirmed by a suggestive chest X-ray and a drop in by ECHO or MUGA. Congestive Heart Failure (CHF) should be treated and monitored according to standard medical practice. At present, there are inadequate data available to assess the prognostic significance of asymptomatic drops of. However, to ensure the safety of patients in the trial, pertuzumab and trastuzumab must be discontinued in all patients for whom a drop of to a value lower than 40% is documented and confirmed with a repeat assessment within 3 weeks of the first assessment, using the same assessment method. For patients whose drops to values < 45% (50% is required for entry into the study), the decision to stop or continue study treatment is based on the algorithm shown below. The incidence of CHF will also be recorded throughout the study. AUTHORISED BY: Dr P Chakraborti PAGE 3 of 6

4 Figure 4 (from Protocol): Asymptomatic decline in : Algorithm for Continuation and Discontinuation of Pertuzumab and Trastuzumab Based on Assessments Assessment 45% > 45% < 40% 40 45% 10% points below baseline or greater Less than 10% points below baseline Hold Study Treatment Repeat in 3 Weeks CONTINUE STUDY TREATMENT < 40% OR 40% 45% and 10% points below baseline or greater > 45% OR 40% 45% and less than 10% points below baseline STOP STUDY TREATMENT RESUME STUDY TREATMENT 7. Infusion associated symptoms and allergic reactions: a) Administration of monoclonal antibodies, including pertuzumab and trastuzumab, may cause infusion-associated symptoms such as fever, chills, hypotension, shortness of breath, skin rashes, headache, nausea, vomiting, or allergic reactions. In general, antibody-associated adverse events are more frequent and severe with the first infusion. Patients with extensive pulmonary disease, e.g., lymphangitis, multiple metastases, recurrent pleural effusions, and those with preexisting pulmonary compromise who are treated with trastuzumab, may be at increased risk of serious infusion-associated symptoms. Therefore, careful consideration must be made before enrolling patients with chronic lung disease into the study. Patients who experience an NCI-CTCAE version 4.0 Grade 4 allergic reaction, acute respiratory distress syndrome (ARDS), or bronchospasm will be discontinued from study treatment. AUTHORISED BY: Dr P Chakraborti PAGE 4 of 6

5 Patients who experience infusion-associated symptoms may be managed by: Slowing or stopping the trastuzumab or pertuzumab infusion. Supportive care with oxygen, beta-agonists, antihistamines, antipyretics, or corticosteroids as appropriate at the investigator's discretion. Premedication with corticosteroids, antihistamines, and antipyretics may be used before subsequent trastuzumab or pertuzumab infusions at the investigator s discretion. If infusion-associated symptoms occur, patients will be monitored until complete resolution of signs and symptoms. Patients should be monitored during each pertuzumab infusion and for 60 minutes following completion of the infusion for any adverse events. Patients should be observed for at least six hours after the start of the first trastuzumab infusion and for two hours after the start of subsequent infusions. Patients who experience infusion-associated symptoms may be subsequently premedicated with paracetamol and chlorphenamine. b) 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. 8. Dose Modifications for Docetaxel as per NCI Common Toxicity Criteria. AUTHORISED BY: Dr P Chakraborti PAGE 5 of 6

6 Febrile neutropenia 20% reduction Docetaxel Stomatitis & Mucositis For Grade III Painful erythema or ulcers requiring IV rehydration resolving to Grade I or less painless ulcers or mild soreness. 20% reduction Docetaxel Peripheral Neuropathy Grade 0,1 no change Grade 2-20% reduction Docetaxel Grade 3 discontinue treatment Cutaneous reactions Grade 0,1,2 no change Grade 3 delay treatment for maximum 2 weeks until at least Grade 1 & restart with 20% reduction of Docetaxel dose Other Toxicities For Grade III toxicity re-treat at 20% dose reduction provided toxicity has resolved to Grade I ore less. If further toxicity an additional reduction may be made. If necessary a delay of the next cycle for up to 2 weeks to allow recovery. if a delay of more than 3 weeks is required for recovery or more than 2 dose reductions are necessary, then the patient should discontinue treatment 9. For details of permitted therapy and prohibited therapy whilst the patient is part of the trial (includes 28 days prior to first study drug administration), please refer to the protocol. 10. For patients experiencing diarrhoea, consider prescribing loperamide. References: 1. Peruse study - Protocol number MO28047 version 5, 20 th November Trastuzumab Summary of Product Characteristics, Roche Products Ltd, last updated 28 th Aug 2018<Accessed > AUTHORISED BY: Dr P Chakraborti PAGE 6 of 6