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Cetuximab-Fluorouracil-Folinic Acid-Oxaliplatin

Description: Chemotherapy Protocol COLORECTAL CANCER CETUXIMAB-FLUOROURACIL-FOLINIC ACID (Modified de Gramont)OXALIPLATIN Regimen • Colorectal Cancer – Cetuximab-Fluorouracil-Folinic Acid (modified de Gramont)-Oxaliplatin Indication • Colorectal cancer with metastases confined to the liver where resection may become possible following treatment • Metastatic or advanced colorectal cancer where surgery to remove the cancer in the colon or rectum has been conducted or is possible • Metastatic or advanced colorectal cancer where the individual is sufficiently fit to undergo surgery to remove the cancer in the colon or rectum and to have a liver resection if it becomes possible to remove the metastasis following cetuximab • WHO performance status 0, 1 Toxicity Drug Cetuximab Fluorouracil Oxaliplatin Adverse Effect Infusion related reactions, interstitial lung disease, skin reactions, electrolyte abnormalities, fatigue, abdominal pain, constipation Palmar-plantar erythrodysesthesia, diarrhoea, mucositis, chest pain Peripheral neuropathy (cumulative), acute laryngopharyngeal dysasthesia (increase duration of infusion) The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFT’s and U&E’s prior to day one of treatment • Patients with complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency are at increased risk of severe and fatal toxicity during treatment with fluorouracil. All patients should be tested for DPD deficiency before initiation (cycle 1) to minimise the risk of these reactions Version 1.5 (October 2020) Page 1 of 11 Colorectal – Cetuximab-Fluorouracil-Folinic Acid (MdG)-Oxaliplatin Dose Modifications The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be reescalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Haematological Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL For haematological toxicity, if the neutrophil count is less than 1.5 109/L or the platelet count is less than 75 109/L, then delay treatment until these levels are achieved. Reinitiate therapy at the full dose for up to a seven day delay or for a delay of more than seven days with 75% of the original dose for thrombocytopenia. If neutropenia is the issue after seven days then omit the bolus fluorouracil for this and subsequent cycles. If a further delay is necessary despite omitting the bolus fluorouracil then reduce the dose of both the infusional fluorouracil and oxaliplatin to 80% of the original dose. If the delay is twenty-one days or longer stop therapy. There is no need to dose adjust the folinic acid for haematological counts. The dose of cetuximab on day eight need not be adjusted for either neutrophil or platelet counts. Liver Impairment Drug Cetuximab Bilirubin μmol/L AST/ALT units Dose (% of original dose) Unlikely to require dose adjustment Fluorouracil More than 85 More than 180 Contra-indicated In moderate hepatic impairment reduce the initial dose by 33%. In severe hepatic impairment reduce the initial dose by 50%. The dose may be increased as tolerated. Oxaliplatin Version 1.5 (October 2020) Limited information available but there is probably little need to adjust the dose. Page 2 of 11 Colorectal – Cetuximab-Fluorouracil-Folinic Acid (MdG)-Oxaliplatin Renal Impairment Drug Creatinine Clearance (ml/min) Dose (% of original dose) Cetuximab Clinical decision. Unlikely to require a dose adjustment Fluorouracil Consider dose adjustment in sever renal impairment Oxaliplatin Moderate renal impairment – treat at normal dose, and monitor renal function. Dose adjust according to toxicity. CrCl < symbols removed and replaced with the corresponding words Regimen name changed to have line between drug names and also added to the regimen summary Folinic Acid added to footer Cetuximab monitoring moved from “additional points” to “administration information” Cetuximab administration changed to 60 minutes on day 8 of cycle 1 1.1 Jan 2011 Oxaliplatin changed to be Dr Debbie Wright Donna Kimber administered in 500ml glucose (Pharmacist) (Pharmacy Technician) 5% Spelling of forth changed to fourth on page 3 Remove duplication of word ‘reaction’ on page 3 Add bolus to statement at bottom of page 8 1 Aug 2010 None Dr Debbie Wright (Pharmacist) Dr Tim Iveson Consultant Medical Oncologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospital NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors which occur as a result of following these guidelines. Version 1.5 (October 2020) Page 11 of 11 Colorectal – Cetuximab-Fluorouracil-Folinic Acid (MdG)-Oxaliplatin
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Colorectal/Cetuximab-Fluorouracil-FolinicAcid-Oxaliplatin.pdf

University Hospital Southampton opens £22m state-of-the-art general intensive care unit

Description: A state-of-the-art intensive care unit for the south's most critically ill patients will be opened at University Hospital Southampton this week.
Url: /AboutTheTrust/Newsandpublications/Latestnews/2020/September/University-Hospital-Southampton-opens-22m-state-of-the-art-general-intensive-care-unit.aspx

Fluorouracil-Folinic Acid-Oxaliplatin

Description: Chemotherapy Protocol COLORECTAL CANCER FLUOROURACIL, FOLINIC ACID (Modified de Gramont) and OXALIPLATIN (FOLFOX) Regimen • Colorectal Cancer– Fluorouracil, Folinic Acid (modified de Gramont) and Oxaliplatin (FOLFOX) Indication • First / second line treatment of advanced / metastatic colorectal cancer. • Adjuvant treatment of stage III colon cancer following surgery. • WHO Performance status 0, 1 Toxicity Drug Fluorouracil Oxaliplatin Adverse Effect Palmar-plantar erythrodysesthesia, diarrhoea, mucositis, chest pain Peripheral neuropathy (cumulative), acute laryngopharyngeal dysasthesia (increase duration of infusion) The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Regimen • FBC, LFT’s and U&E’s prior to day one of treatment • Patients with complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency are at increased risk of severe and fatal toxicity during treatment with fluorouracil. All patients should be tested for DPD deficiency before initiation (cycle 1) to minimise the risk of these reactions Dose Modifications The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be reescalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Version 1.4 (November 2020) Page 1 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX) Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Haematological Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL For haematological toxicity, if the neutrophil count is less than 1.5 109/L or the platelet count less than 75 109/L, delay treatment until these levels are achieved. Reinitiate therapy at the full dose for up to a 7 day delay or, for a delay of more than 7 days, with 75% of the original dose for thrombocytopenia. If neutropenia is the issue after 7 days omit the bolus fluorouracil for this and subsequent cycles. If a further delay is necessary despite omitting the bolus fluorouracil then reduce the dose of both the infusional fluorouracil and oxaliplatin to 80% of the original dose. If the delay is ≥ 21 days stop therapy. There is no need to dose adjust the folinic acid for haematological counts. Liver Impairment Drug Fluorouracil Bilirubin μmol/L More than 85 AST/ALT units More than 180 Dose (% of original dose) Contra-indicated In moderate hepatic impairment reduce the initial dose by 33%. In severe hepatic impairment reduce the initial dose by 50%. The dose may be increased as tolerated. Oxaliplatin Limited information available but there is probably little need to adjust the dose. Version 1.4 (November 2020) Page 2 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX) Renal Impairment Drug Creatinine Clearance (ml/min) Dose (% of original dose) Fluorouracil Consider dose adjustment in sever renal impairment Oxaliplatin Moderate renal impairment – treat at normal dose, and monitor renal function. Dose adjust according to toxicity. CrCl <20m/min –dose reduce Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Dose limiting toxicities include diarrhoea, abdominal pain, emesis, stomatitis, palmar-plantar erythrodysesthesia and neurosensory toxicities among others. If any NCI-CTC grade 1 toxicity occurs treatment should be continued, without interruption, at the full dose. For toxicities at NCI-CTC grade 3 or above treatment should be withheld until recovery to NCI-CTC grade 1 then re-started if medically appropriate. If recovery takes 21 days or longer stop treatment. Fluorouracil Diarrhoea occurring for the first time at NCI-CTC grade 2 should be approached by withholding the fluorouracil until it has resolved to NCI-CTC grade 1. Treatment can then be re-started at full dose. Treatment should again be delayed on development of a second NCI-CTC grade 2 diarrhoea and the fluorouracil re-started at 75% of the original dose when it has resolved to NCI-CTC grade 1. After resolution of a third episode of NCI-CTC grade 2 diarrhoea to NCI-CTC grade 1 the fluorouracil should be re-started using 50% of the original dose. On appearance of a NCI-CTC grade 3 diarrhoea withhold fluorouracil until it has resolved to NCI-CTC grade 1 and re-start treatment using 75% of the original dose. After a second episode at NCI-CTC grade 3 wait until the diarrhoea has resolved to NCI-CTC grade 1 and resume the fluorouracil using 50% of the original dose. For a third appearance of NCI-CTC grade 3 diarrhoea or the development of grade 4 toxicity at ant time stop fluorouracil therapy. Version 1.4 (November 2020) Page 3 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX) Oxaliplatin If the neurosensory toxicity is NCI-CTC grade 1–2 and lasts less than 7 days administer full dose oxaliplatin. If the toxicity is NCI-CTC grade 2 and persists for more than 7 days reduce the oxaliplatin dose to 75mg/m2. Oxaliplatin should be discontinued for neurosensory toxicities NCI-CTC grade 3 or above. If NCI-CTC grade 3-4 diarrhoea or stomatitis recurs despite appropriate reduction in the fluorouracil dose the oxaliplatin dose should be reduced to 75mg/m2. There are rare case reports of acute interstitial lung disease or lung fibrosis in association with oxaliplatin. Where an unexplained respiratory symptom occurs stop treatment until pulmonary investigations have been conducted to exclude an interstitial cause. Regimen 14 day cycle for 6 - 12 cycles Drug Folinic Acid Oxaliplatin Fluorouracil Fluorouracil Dose 350mg 85mg/m2 400mg/m2 2400mg/m2 Days 1 1 1 1 Administration Intravenous infusion in 250ml glucose 5% over 120 minutes Intravenous infusion in 500ml glucose 5% over 120 minutes Intravenous bolus over 10 minutes Intravenous infusion over 46 hours Dose Information • Fluorouracil will be dose banded in accordance with the national dose bands (25mg/ml PM bolus and 50mg/ml infusion) • Oxaliplatin will be dose banded in accordance with the national dose bands (5mg/ml) Administration Information Extravasation • Fluorouracil – inflammitant • Oxaliplatin - exfoliant Other • Central venous access and use of an ambulatory infusion pump is required. Additional Therapy • Antiemetics 15-30 minutes prior to chemotherapy Version 1.4 (November 2020) Page 4 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX) - dexamethasone 8mg oral or intravenous - ondansetron 8mg oral or intravenous As take home medication; - dexamethasone 4mg twice a day for 3 days oral - metoclopramide 10mg three times a day when required oral • Oral loperamide 4mg after the first loose stool then 2-4mg four times a day when required for the relief of diarrhoea (maximum 16mg/24 hours). • Gastric protection with a proton pump inhibitor or H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed Additional Information • A glucose 5% flush should be administered before and after the oxaliplatin • The folinic acid may be replaced with calcium levofolinate 175mg intravenous infusion in 250ml glucose 5% over 120 minutes References 1. Cheeseman SL, Joel SP, Chester JD et al. A “modified de Gramont” regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer 2002; 87 (4): 393-9. Version 1.4 (November 2020) Page 5 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX) REGIMEN SUMMARY Day One 1. Dexamethasone 8mg oral or intravenous 2. Ondansetron 8mg oral or intravenous 3. Oxaliplatin 85mg/m2 intravenous infusion in 500ml glucose 5% over 120 minutes 4. Folinic Acid 350mg in 250ml glucose 5% over 120 minutes intravenous infusion 5. Fluorouracil 400mg/m2 intravenous bolus over 10 minutes 6. Fluorouracil 2400mg/m2 intravenous infusion over 46 hours Take Home Medicines 7. Dexamethasone 4mg twice a day for 3 days oral starting on day two of the cycle 8. Metoclopramide 10mg three times a day when required oral Version 1.4 (November 2020) Page 6 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX) DOCUMENT CONTROL Version Date Amendment Written/ By Approved By Updated monitoring with DPD 1.4 Nov 2020 testing Dose banding updated Coding removed Donna Kimber Pharmacy Technician Rebecca Wills Pharmacist Header changed Intravenous added to supportive therapies 1.3 PO changed to oral May 2014 Metoclopramide dose changed to 10mg Dr Debbie Wright Pharmacist Donna Kimber Pharmacy Technician Dexamethasone TTO clarified Coding updated Disclaimer added Document control table added. OPCS procurement code changed from X70.5 to X70.4. Duration of administration of fluorouracil bolus changed to 10 1.2 January minutes in regimen and regimen 2013 summary. Rebecca Wills Pharmacist Dr Debbie Wright Pharmacist Order of administration changed in regimen summary – folinic acid now after oxaliplatin. Information on dose, liver and rnal impairment put into tables. 1.1 January 2011 Oxaliplatin changed to be administered in 500ml glucose 5%. Dr Debbie Wright Pharmacist Donna Kimber Pharmacy Technician 1 August 2010 None Dr Debbie Wright Pharmacist Dr Tim Iveson Consultant Medical Oncologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors which occur as a result of following these guidelines. Version 1.4 (November 2020) Page 7 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX) Version 1.4 (November 2020) Page 8 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG) and Oxaliplatin (FOLFOX)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Colorectal/Fluorouracil-FolinicAcid-Oxaliplatin.pdf

Fluorouracil-FolinicAcid(MdG)-Oxaliplatin-Panitumumab

Description: Chemotherapy Protocol COLORECTAL CANCER FLUOROURACIL, FOLINIC ACID (Modified de Gramont), OXALIPLATIN and PANITUMUMAB (FOLFOX-Panitumumab) Regimen • Colorectal Cancer– Fluorouracil, Folinic Acid (modified de Gramont), Oxaliplatin and Panitumumab (FOLFOX-Panitumumab) Indication • First metastatic colorectal cancer where the following criteria are met; - the tumour is wild type RAS - no prior exposure to either cetuximab or panitumumab • WHO Performance status 0, 1 Toxicity Drug Fluorouracil Oxaliplatin Panitumumab Adverse Effect Palmar-plantar erythrodysesthesia, diarrhoea, mucositis, chest pain Peripheral neuropathy (cumulative), acute laryngopharyngeal dysasthesia (increase duration of infusion) Infusion related reactions, interstitial lung disease, skin reactions, electrolyte abnormalities, fatigue, abdominal pain, constipation The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Regimen • FBC, LFT’s and U&E’s prior to day one of treatment. • Prior to starting therapy confirm a positive wild type RAS status • Patients with complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency are at increased risk of severe and fatal toxicity during treatment with fluorouracil. All patients should be tested for DPD deficiency before initiation (cycle 1) to minimise the risk of these reactions Dose Modifications The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. Version 1.1 (November 2020) Page 1 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab) In principle all dose reductions due to adverse drug reactions should not be reescalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Haematological Consider blood transfusion or erythropoietin if the patient is symptomatic of anaemia or has a haemoglobin of less than 8g/dL For haematological toxicity, if the neutrophil count is less than 1.5 109/L or the platelet count is less than 75 109/L, delay treatment until these levels are achieved. Reinitiate therapy at the full dose for up to a seven day delay or, for a delay of more than seven days, with 75% of the original dose for thrombocytopenia. If neutropenia is the issue then after seven days omit the bolus fluorouracil for this and subsequent cycles. If a further delay is necessary despite omitting the bolus fluorouracil then reduce the dose of both the infusional fluorouracil and oxaliplatin to 80% of the original dose. If the delay is twenty-one days or more stop therapy. The panitumumab dose rarely needs to be reduced for haematological toxixity but may be delayed. There is no need to dose adjust the folinic acid for haematological counts. Liver Impairment Drug Fluorouracil Bilirubin μmol/L More than 85 AST/ALT units More than 180 Dose (% of original dose) Contra-indicated In moderate hepatic impairment reduce the initial dose by 33%. In severe hepatic impairment reduce the initial dose by 50%. The dose may be increased as tolerated. Oxaliplatin Limited information available but there is probably little need to adjust the dose. Panitumumab No information available Version 1.1 (November 2020) Page 2 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab) Renal Impairment Drug Creatinine Clearance (ml/min) Dose (% of original dose) Fluorouracil Consider dose adjustment in sever renal impairment Oxaliplatin For moderate renal impairment, treat at normal dose, and monitor renal function. Dose adjust according to toxicity. If the CrCl is less than 20m/min then dose reduce Panitumumab No information available Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Dose limiting toxicities include diarrhoea, abdominal pain, emesis, stomatitis, palmar-plantar erythrodysesthesia and neurosensory toxicities among others. If any NCI-CTC grade 1 toxicity occurs treatment should be continued, without interruption, at the full dose. For toxicities at NCI-CTC grade 3 or above treatment should be withheld until recovery to NCI-CTC grade 1 then re-started if medically appropriate. If recovery takes 21 days or longer stop treatment. Fluorouracil Diarrhoea occurring for the first time at NCI-CTC grade 2 should be approached by withholding the fluorouracil until it has resolved to NCI-CTC grade 1. Treatment can then be re-started at full dose. Treatment should again be delayed on development of a second NCI-CTC grade 2 diarrhoea and the fluorouracil re-started at 75% of the original dose when it has resolved to NCI-CTC grade 1. After resolution of a third episode of NCI-CTC grade 2 diarrhoea to NCI-CTC grade 1 the fluorouracil should be re-started using 50% of the original dose. On appearance of a NCI-CTC grade 3 diarrhoea withhold fluorouracil until it has resolved to NCI-CTC grade 1 and re-start treatment using 75% of the original dose. After a second episode at NCI-CTC grade 3 wait until the diarrhoea has resolved to NCI-CTC grade 1 and resume the fluorouracil using 50% of the original dose. For a third appearance of NCI-CTC grade 3 diarrhoea or the development of grade 4 toxicity at ant time stop fluorouracil therapy. Version 1.1 (November 2020) Page 3 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab) Oxaliplatin If the neurosensory toxicity is NCI-CTC grade 1–2 and lasts less than 7 days administer full dose oxaliplatin. If the toxicity is NCI-CTC grade 2 and persists for more than 7 days reduce the oxaliplatin dose to 75mg/m2. Oxaliplatin should be discontinued for neurosensory toxicities NCI-CTC grade 3 or above. If NCI-CTC grade 3-4 diarrhoea or stomatitis recurs despite appropriate reduction in the fluorouracil dose the oxaliplatin dose should be reduced to 75mg/m2. There are rare case reports of acute interstitial lung disease or lung fibrosis in association with oxaliplatin. Where an unexplained respiratory symptom occurs stop treatment until pulmonary investigations have been conducted to exclude an interstitial cause. Panitumumab An acniform skin rash occurs in over 90% of those receiving panitumumab. The onset is normally within three weeks of starting therapy and often resolves after week twelve. Please refer to local guidelines for the treatment of this reaction. Alternatively, for a NCI-CTC grade 1-2 reaction use symptomatic treatments such as topical or oral antibiotics and continue with the panitumumab. For a NCI-CTC grade 3 toxicity delay treatment until the toxicity resolves to NCI-CTC grade 2 or below. Re-instate therapy using 50% of the original dose. If the reaction does not recur escalate the dose in 25% increments as tolerated until the recommended dose is reached. If the reactions do not resolve to less than NCI-CTC grade 2 after withholding up to two doses or if the skin toxicity recurs or becomes intolerable at 50% of the original dose discontinue treatment. UV radiation may worsen skin reactions. Sun safety practices should be followed during and for up to two months after the end of treatment. Stop treatment if there is a confirmed pneumonitis. Regimen 14 day cycle for 6 cycles Drug Folinic Acid Oxaliplatin Fluorouracil Fluorouracil Panitumumab Dose 350mg 85mg/m2 (maximum dose 170mg) 400mg/m2 2400mg/m2 6mg/kg Days Administration 1 Intravenous infusion in 250ml glucose 5% over 120 minutes 1 Intravenous infusion in 500ml glucose 5% over 120 minutes 1 Intravenous bolus over 10 minutes 1 Intravenous infusion over 46 hours Intravenous infusion in 100ml sodium 1 chloride 0.9% over 60 minutes (see administration instructions) Version 1.1 (November 2020) Page 4 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab) Dose Information • Fluorouracil will be dose banded in accordance with the national dose bands (25mg/ml PM bolus and 50mg/ml infusion) • Oxaliplatin will be dose banded in accordance with the national dose bands (5mg/ml) • Oxaliplatin dose will be capped at 170mg. • Panitumumab will be dose banded in accordance with the national dose bands (20mg/ml NS) Administration Information Extravasation • Fluorouracil – inflammitant • Oxaliplatin – exfoliant • Panitumumab - neutral Other • Central venous access and use of an ambulatory infusion pump may be required. • Panitumumab must be administered using a 0.22 micron in-line filter • Doses of 1000mg and above must be administered over 90 minutes in 150ml sodium chloride 0.9% Additional Therapy • Antiemetics 15-30 minutes prior to chemotherapy - dexamethasone 8mg oral or intravenous - ondansetron 8mg oral or intravenous As take home medication; - dexamethasone 4mg twice a day for 3 days oral - metoclopramide 10mg three times a day when required oral • Oral loperamide 4mg after the first loose stool then 2-4mg four times a day when required for the relief of diarrhoea (maximum 16mg/24 hours). • Prophylaxis for skin rash according to local formulary choices. For example; Version 1.1 (November 2020) Page 5 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab) - doxycycline 100mg twice a day for 14 days oral - lymecycline 408mg once a day for 14 days oral • Gastric protection with a proton pump inhibitor or H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed Additional Information • A glucose 5% flush should be administered before and after the oxaliplatin • The folinic acid may be replaced with calcium levofolinate 175mg intravenous infusion in 250ml glucose 5% over 120 minutes References 1. Douillard JY, Oliner KS, Siena S et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369 (11): 1023-1034. Version 1.1 (November 2020) Page 6 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab) REGIMEN SUMMARY Flourouracil-Folinic Acid (MdG)-Oxaliplatin-Panitumumab (FOLFOXPanitumumab) Day One 1. Panitumumab 6mg/kg intravenous infusion in 100ml sodium chloride 0.9% over 60 minutes* 2. Dexamethasone 8mg oral or intravenous 3. Ondansetron 8mg oral or intravenous 4. Oxaliplatin 85mg/m2 intravenous infusion in 500ml glucose 5% over 120 minutes 5. Folinic Acid 350mg in 250ml glucose 5% over 120 minutes intravenous infusion 6. Fluorouracil 400mg/m2 intravenous bolus over 10 minutes 7. Fluorouracil 2400mg/m2 intravenous infusion over 46 hours Take Home Medicines 7. Dexamethasone 4mg twice a day for 3 days oral starting on day two of the cycle 8. Metoclopramide 10mg three times a day when required oral 9. Skin Rash Prophylaxis Administration Instructions For the prevention of skin reactions according to local formulary choice; - doxycycline 100mg twice a day for 14 days oral - lymecycline 408mg once a day for 14 days oral *Please refer to the administration instructions Version 1.1 (November 2020) Page 7 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab) DOCUMENT CONTROL Version Date Amendment Written/ By Approved By Updated monitoring with DPD 1.1 Nov 2020 testing Dose banding updated Coding removed 1 May 2016 None Donna Kimber Pharmacy Technician Dr Deborah Wright Pharmacist Rebecca Wills Pharmacist Dr Tim Iveson Consultant Medical Oncologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors which occur as a result of following these guidelines. Version 1.1 (November 2020) Page 8 of 8 Colorectal – Fluorouracil, Folinic Acid (MdG), Oxaliplatin, Panitumumab (FOLFOX-Panitumumab)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Colorectal/Fluorouracil-FolinicAcidMdG-Oxaliplatin-Panitumumab.pdf

BEACON protocol v8.0 07Mar2023 signed

Description: A randomised phase IIb trial of BE AC v izumab added to Temozolomide O ± Irin tecan for children with N refractory/relapsed euroblastoma Version 8.0 dated 07-Mar-2023 Dinutuximab beta amendment Coordinating Sponsor: Sponsor Protocol Number: CAS Code: EudraCT Number: ISRCTN Reference Number: ITCC Number: Roche Study Reference Number: Email: University of Birmingham RG_ 11-087 BN2008 2012-000072-42 40708286 032 MO28245 beacon@trials.bham.ac.uk This application is supported by the facilities funded through Birmingham Science City: Translational Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) funded project which forms part of the Science City University of Warwick and University of Birmingham Research Alliance. BEACON-Neuroblastoma Protocol_vn 8.0_vd 07Mar2023 Page1 of 157 BEACON-Neuroblastoma Trial Protocol AMENDMENTS The following amendments and/or administrative changes have been made to this protocol since the implementation of the first approved version Amendment Date of number amendment Protocol version number Type of amendment SA 1 29-Jan-2013 2.0 Substantial Amendment N/A 23-Apr-2013 2.0a Non-Substantial Amendment N/A 01-Jul-2013 2.0b Non-Substantial Amendment Summary of amendment Introduction of the recommendation of weekly monitoring of blood counts for all patients receiving irinotecan. Addition of planned vaccination with live vaccination to exclusion criteria and prohibited medications section. ITCC Number has been corrected. Roche Study Reference Number and ISRCTN Reference Number have been added. Contact details for Plasma & Tumour Angiogenesis-Related Biomarkers have been amended. Table numbers have been corrected. Addition of guidance for research bone marrow sampling in Schedule of Activities table and sections 7.4.2.2 and 7.5.2. Addition of paragraph to sections 7.2, 7.6.1 – 7.6.4 detailing arrangements for handling dose modifications for Irinotecan + Temozolomide for patients receiving Bevacizumab. Discontinuation rules for osteonecrosis of the jaw and eye disorders added to table 13 in section 7.6.4. Correction to table number references in section 7.6.3. Clarification made in section 13.4.1 concerning Planned Interim Analysis. SA 3 06-Oct-2014 4.0 Substantial Amendment Changes to the Trial Personnel section of the protocol to include the addition of contact details for Denmark and Ireland Lead Investigators. Amendments to reflect the changes in study sampling requirements to Trial Synopsis, Schedule of Activities table and sections 1.2.6, 2.1, 2.2, 5.1, 5.2, 7.3, 7.4.2 and 7.5. Amendment to exclusion criteria in Trial Synopsis and section 4.2. Changes to the Schedule of Activities table to include the addition of an echocardiogram to be performed at screening and Tanner staging at screening and yearly in follow up. Changes to the time line for measuring renal function prior to commencing treatment in the Trial Synopsis, Schedule of Activities and section 4.1. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 3 of 157 BEACON-Neuroblastoma Trial SA 4 06-Oct-2014 4.0 SA 5 30-Jul-2015 5.0 Substantial Amendment Substantial Amendment Protocol Option to fax emergency randomisation removed. Telephone only in section 6.2 Changes to guidelines in section 7.2 for dose calculation in patients whose weight exceeds the 98th centile for age. Removal of enhanced data collection for Adverse Events of Special Interest (AESI) in section 7.6 and 9.1.2. Addition of option to extend treatment delay with agreement from Sponsor in Section 7.6.1 Addition of necrotising fasciitis as an adverse event requiring bevacizumab discontinuation in section 7.6.4. Changes to section 7.10 concerning the documenting of concomitant medications in patient medical notes and administration of bisphosphonates. Changes to section 9.1 regarding reporting of laboratory adverse events. Clarification on the arrangements for Follow Up Form completion for patients who do not require further follow up visits in section 11. Changes to bevacizumab and irinotecan preparation and dispensing guidelines in sections 8.2.4 and 8.3.3. Clarification on fasting arrangements prior to temozolomide administration added to section 8.4.3. Changes to events that should be reported on an Expected SAR Form in section 9.1.3.1. Clarification on SAEs that should be reported to F.Hoffman-La Roche Ltd in section 9.2.6 Addition of Trial Management Group meeting frequency in section 14.4. Changes to the wording of irinotecan randomisation in section 13.4.2. Addition of guidelines for dose reduction and discontinuation of temozolomide for liver toxicity in tables 8, 9, 10 & 11. Reference to the National Coordinating Centres has been changed to National CoSponsor throughout. Reference to Sponsor has been changed to Coordinating Sponsor. Change of Chief Investigator to Professor Pamela Kearns. Change of Principal Investigator at Royal Marsden Hospital to Dr Sucheta Vaidya. No changes made to the Protocol version. Chief Investigator and UK Lead Investigator changed to Dr Lucas Moreno Switzerland details added Schedule of events table amended for End Of Treatment clarity BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 4 of 157 BEACON-Neuroblastoma Trial N/A 23-Sep-2015 5.0a SA 6 16-Jan-2019 6.0a Protocol Topotecan added to the study as a new trial question and 2 new randomisation arms. The following sections are amended accordingly: Synopsis (Primary Objectives, sample size, Trial Duration, Trial therapy) Section 1 Background and rationale (Trial rationale) Section 3 Trial design (Randomisation) Section7.1 and 7.2 Treatment details Section7.6.1 Dose modifications Table 6 amended, Tables 11 and 12 added Section 8.4 Pharmaceutical Information Section 13 Statistical considerations The following changes were made to the Eligibility: Inclusion criteria – further details regarding birth control Exclusion criteria – Defined wash out period following prior IMP according to IMP half-life or 14 days. Lifestyle guidelines - further details regarding birth control Section 7.6 Dose modifications Figure 1 – reference to “chemo” changed to Temozolomide/Irinotecan/Topotecan” for clarity Section 8.2.4 Reference to “chemo” removed for clarity Section 7.6.4 AEs requiring Bevacizumab discontinuation – additional AEs added following Bevacizumab IB v22 Addendum Additional mRNA and exploratory sampling. Non-Substantial Amendment Substantial amendment The requirement for confirmatory scans was removed from the Schedule of Activities and Response assessment section 7.4.3. Lead Investigator for France amended to Dr Marion Gambart Minor wording corrections and clarifications Schedule of events table corrected Introduction of two new treatment arms (dinutuximab beta) for additional 64 patients Addition of eligibility criteria, schedule of events, treatment details, duration, cross over and dose modification details for new dinutuximab beta arms Adaptation of objectives, trial design, supporting treatment, pharmaceutical information and statistical consideration sections with new, relevant information. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 5 of 157 BEACON-Neuroblastoma Trial N/A 11-Apr-2019 6.0b SA 7 07-Feb-2020 7.0 SA 22 07-Mar-2023 8.0 Protocol Non-Substantial Amendment Substantial Amendment Substantial Amendment Minor wording corrections and clarifications Version amended from 6.0 to 6.0a to add. Additional rationale to update typographical errors.) Trial Synopsis: Clarification of recruitment targets Clarification of Section 10 title: “Dinutuximab beta and topotecan randomisations” Clarification that not all biological studies will be open at any one time (Section 10.2 and 15.5) Minor wording corrections and clarifications Urgent Safety Measure – implemented on 28th January 2020 Closure of Temozolomide (T) and Dinutuximab beta and Temozolomide (dBT) arms with immediate effect. Section 1.1 Background Section 1.2.3 Benefit Risk assessment Section 3.1 Randomisation Section 10 Headings changed Section 10.3 Trial therapy Update of contact details Change of definition of End of Trial (Section 21). Protocol previously defined two stages of end of trial (6 months after last patient completes treatment and 12 months after last data capture after 5 years follow up). This has been combined into one End of Trial definition: 6 months after last patient last visit (i.e. after 5 years follow up) Also addition of option to email SAE form (Section 18.2.1.2) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 6 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL PERSONNEL Chief Investigator: Co-Investigators: Exploratory Biomarkers Dr Lucas Moreno Dr. Lucas Moreno, MD, PhD Director Paediatric Oncology & Haematology Division Vall d’Hebron Barcelona Hospital Campus Passeig de la Vall d’Hebron, 119-129, 08035, Barcelona, Spain  +34 93 489 3000  +34 93 489 4060  lucas.moreno@vhebron.net Professor Keith Wheatley Professor of Clinical Trials Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 415 9119  k.wheatley@bham.ac.uk Dr Juliet Gray Associate Professor and Consultant in Paediatric Oncology Southampton Children’s Hospital Tremona Road Southampton SO16 6YD  +44 (0) 790 1507929  juliet.gray@uhs.nhs.uk Dr Gudrun Schleiermacher Senior Scientist Institute Curie 26 rue d'Ulm 75248 Paris cedex 05 France  +33 (0)1 56 24 45 50  +33 (0)1 56 24 66 30  gudrun.schleiermacher@curie.net Professor Louis Chesler Paediatric Tumour Biology Team Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0) 208 722 4035 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 7 of 157 BEACON-Neuroblastoma Trial Protocol  louis.chesler@icr.ac.uk Functional Imaging Study: Professor Andrew Peet Institute of Child Health University of Birmingham Whittall Street Birmingham, UK B4 6NH  +44 (0) 121 333 8234  +44 (0) 121 333 8241  a.peet@bham.ac.uk Dr Dow-Mu Koh Consultant Radiologist in Functional Imaging Royal Marsden Hospital Downs Road, Sutton, Surrey, UK SM2 5PT  +44 (0) 208 6613857  dow-mu.koh@icr.ac.uk Professor Martin Leach Co-Director, Cancer Research UK and EPSRC Centre for Cancer Imaging, Director, NIHR Clinical Research Facility Deputy Head, Division of Radiotherapy and Imaging Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0 208 661 3338  Martin.Leach@icr.ac.uk Molecular Monitoring mRNA Study: Professor Sue Burchill Leeds Institute of Cancer & Pathology St. James University Hospital Beckett Street Leeds, UK LS9 7TF  +44 (0) 113 206 5873  +44 (0) 113 242 9886  S.A.Burchill@leeds.ac.uk Professor Walter Gregory Clinical Trials Research Unit (CTRU) University of Leeds Clinical Trials Research House 71-75 Clarendon Road Leeds LS2 9PH  +44 (0) 113 343 1489  +44 (0) 113 343 1471 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 8 of 157 BEACON-Neuroblastoma Trial Protocol Trial Statistician: Trial Coordinator & Trial Office: Randomisation Service: SAE Reporting:  W.M.Gregory@leeds.ac.uk Miss Grace Holt Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 8328  +44 (0)121 414 3700  G.C.Holt@bham.ac.uk Miss Punam Mistry Children’s Cancer Trials Team Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  beacon@trials.bham.ac.uk Provided by the CRCTU at the University of Birmingham Randomisation should be performed by sites online at: https://www.cancertrials.bham.ac.uk/BEACONLive In case of any problems with online randomisation, randomisation can be performed over the phone by the CRCTU on: 0800 371 969 or +44 (0)121 414 3366 SAEs should be faxed to the BEACON-Neuroblastoma Trial Office, CRCTU, University of Birmingham, UK  + 44 (0)121 414 9520 or +44 (0)121 414 3700 National Coordinating Investigators: Austria – Lead Investigator: Prof Dr Ruth Ladenstein St. Anna Children’s Hospital and CCRI /Studies and Statistics Department for Integrated Research and Projects (S²IRP) Kinderspitalgasse 6, Zimmermannplatz 10 A-1090 Vienna Austria +43-1-40470-4750  +43-1- 40470- 7430  ruth.ladenstein@ccri.at BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 9 of 157 BEACON-Neuroblastoma Trial Belgium Lead Investigator: Prof Genevieve Laureys Ghent University Hospital 9000 Ghent De Pinterlaan 185 Belgium  +32 93 32 34 48  genevieve.laureys@uzgent.be Denmark – Lead Investigator: Dr Karsten Nysom Dept. of Paediatrics & Adolescent Medicine Rigshospitalet Blegdamsvej 9 DK2100 Copenhagen Denmark  +45 35 45 08 09  +45 35 45 50 55  Karsten.nysom@regionh.dk France – Lead Investigator: Dr Marion Gambart Unité d'Hémato-Oncologie Hôpital des Enfants 330, avenue de Grande Bretagne TSA 70034 31059 Toulouse Cedex France  +33 (0)5 34 55 86 11  +33 (0)5 34 55 86 12  gambart.m@chu-toulouse.fr Germany - Lead Investigator: Dr. Simone Hettmer Zentrum für Kinder- und Jugendmedizin UNIVERSITÄTSKLINIKUM FREIBURG Mathildenstr. 1, 79106 Freiburg Germany  +49 761 270-43000  +49 761 270-45180  simone.hettmer@uniklinik-freiburg.de Ireland – Lead Investigator: Dr Cormac Owens Our Lady’s Children’s Hospital Crumlin Road, Crumlin Dublin 12 Ireland  +35314096659  +35313453041  Cormac.owens@olchc.ie Protocol BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 10 of 157 BEACON-Neuroblastoma Trial Protocol Italy – Lead Investigator: Dr. Aurora Castellano U.O.Oncoematologia Ospedale Pediatrico Bambino Gesù Pzza S. Onofrio 4 00165 Roma Italy +39 06 68592957-2678  +39 06 68592826  aurora.castellano@opbg.net Netherlands – Lead Investigator: Dr. C Michel Zwaan Erasmus Medical Center Sophia’s Children's Hospital Dr. Molewaterplein 60 3015 GJ Rotterdam +31 (0) 10 703 6691  +31(0) 10 703 6681  c.m.zwaan@erasmusmc.nl Spain – Lead Investigator: Dr. Victoria Castel Instituto de Investigación Sanitaria Unidad de Oncología Pediátrica Hospital Universitario La Fe Bulevar Sur, S/N 46026 Valencia Spain +34 963862758 Ext 50040  +34 963494416  castel_vic@gva.es Switzerland – Lead Investigator: Dr. Nicolas Gerber University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland +41 44 266 31 17  +41 44 266 34 61  Nicolas.gerber@kispi.uzh.ch UK – Lead Investigator: Dr Lucas Moreno Honorary Research Fellow University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  lucas.moreno@vhebron.net, lmorenom@ext.cnio.es BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 11 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL SYNOPSIS Title A randomised phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma – BEACON-Neuroblastoma Trial Trial Design A phase II, randomised, open label, international multicentre 3x2 factorial trial. The dinutuximab beta amendment did utilise a 2x2 factorial design it will now be a simple two-way randomisation. Objectives Primary: - To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan + temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma - To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma - To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma (“topotecan randomisation”) - To test whether dinutuximab beta added to a backbone chemotherapy regimen (temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma (“dinutuximab beta randomisation”) Secondary: - To evaluate the safety of the regimens Tertiary: - To undertake preliminary evaluation of the changes in magnetic resonance imaging (MRI) derived functional imaging biomarkers of angiogenesis - To undertake preliminary evaluation of the role of circulating mRNA levels for tyrosine hydroxylase (TH), paired-like homeobox 2b (PHOX2B) and doublecortin (DCX) as prognostic/predictive biomarkers in this refractory/relapsed setting - To undertake a preliminary evaluation of the role of tumour molecular profiles in blood and archival tumour tissue profiles as prognostic and predictive biomarkers - To undertake a preliminary evaluation of biomarkers of response to anti-GD2 therapy (Fc/KIR polymorphisms, Antibody Dependant Cell-Mediated Cytotoxicity (ADCC) and Anti-Drug Antibodies (ADAs) and of dinutuximab beta pharmacokinetics (PK) Outcome Measures Primary Endpoint: - Best response (Complete Response [CR] or Partial Response [PR]) [1] at any time during the first 6 cycles of trial treatment - For the bevacizumab part 2 only: Progression-free survival (PFS) Secondary Endpoints: - Safety of the regimens: Incidence and severity of Adverse Events (AE)s - PFS - Overall survival (OS) - Event-free survival (EFS) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 12 of 157 BEACON-Neuroblastoma Trial Protocol Exploratory/Tertiary Endpoints: - Changes in (MRI) derived functional imaging biomarkers of angiogenesis measured by quantitative dynamic contrast enhanced (DCE) MRI: primary biomarkers will be the transfer constant Ktrans [min-1] and initial area under the gadolinium uptake curve from 0 to 60 seconds (IAUGC60, mM Gd min) and secondary biomarkers will be tumour apparent diffusion coefficient (ADC, 10-6 cm2 s-1), native T1 and T2 relaxation times (ms) and transverse relaxation rate R2* - Changes in circulating mRNA levels for TH, PHOX2B and DCX in bone marrow and blood samples - Pilot descriptive study of angiogenesis and neuroblastoma markers that may include O6methylguanine-methyltransferase (MGMT) status, immunohistochemistry and immunofluorescence markers on tumour samples (such as microvessel density (MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from tissue sections for tumour mutation screening and tumour expression profiling - A preliminary correlation of the different biomarkers [Fc/KIR polymorphisms, Antibody – Dependent Cellular Toxicity (ADCC), and Anti-Drug Antibodies (ADAs)] will be made with parameters of anti-tumour activity (response rate, PFS and OS). PK parameters (dinutuximab beta trough levels) for this chemo-immunotherapy regimen will be described. Patient Population Children and young adults aged 1 to 21 years of age with relapsed/refractory neuroblastoma. Sample Size Approximately 224 patients, including 160 for the bevacizumab randomisation and 64 for the dinutuximab beta amendment. Trial Duration 8 years of patient recruitment, 5 years of patient follow up BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 13 of 157 BEACON-Neuroblastoma Trial Protocol Abbreviations ADA ANTI-DRUG ANTIBODIES ADCC ANTIBODY – DEPENDENT CELL-MEDIATED CYTOTOXICITY AE ADVERSE EVENT AESI ADVERSE EVENT OF SPECIAL INTEREST AFSAPPS COMPETENT AUTHORITY FOR FRANCE ALT ALANINE AMINOTRANSFERASE ANC ABSOLUTE NEUTROPHIL COUNT APPT ACTIVATED PARTIAL THROMBOPLASTIN TIME ASCT AUTOLOGOUS STEM CELL TRANSPLANTATION AST ASPARTATE AMINOTRANSFERASE AUC AREA UNDER THE CURVE AR ADVERSE REACTION BIT BEVACIZUMAB + IRINOTECAN + TEMOZOLOMIDE ARM BM BONE MARROW BP BLOOD PRESSURE BSA BODY SURFACE AREA BT BEVACIZUMAB + TEMOZOLOMIDE ARM BTTo BEVACIZUMAB + TEMOZOLOMIDE + TOPOTECAN ARM CI CHIEF INVESTIGATOR CIs CONFIDENCE INTERVALS COG CHILDREN’S ONCOLOGY GROUP CNS CENTRAL NERVOUS SYSTEM CR COMPLETE RESPONSE CRF CASE REPORT FORM CR UK CANCER RESEARCH UK CRCTU CANCER RESEARCH UK CLINICAL TRIALS UNIT (UNIVERSITY OF BIRMINGHAM) CRN CLINICAL RESEARCH NETWORK CSR CLINICAL STUDY REPORT CT COMPUTERISED TOMOGRAPHY CTC COMMON TERMINOLOGY CRITERIA CTCAE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS CXR CHEST X-RAY dBT DINUTUXIMAB BETA + TEMOZOLOMIDE ARM dBTTo DINUTUXIMAB BETA + TEMOZOLOMIDE + TOPOTECAN ARM DCX DOUBLECORTIN DLT DOSE LIMITING TOXICITY DMC DATA MONITORING COMMITTEE DNA DEOXYRIBONUCLEIC ACID ECHO ECHOCARDIOGRAM ECOG EASTERN COOPERATIVE ONCOLOGY GROUP EFS EVENT FREE SURVIVAL EMA EUROPEAN MEDICINES AGENCY ERDC ELECTRONIC REMOTE DATA CAPTURE EOT END OF TREATMENT FFPE FORMALIN-FIXED PARAFFIN EMBEDDED GCP GOOD CLINICAL PRACTICE G-CSF GRANULOCYTE COLONY STIMULATING FACTOR BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 14 of 157 BEACON-Neuroblastoma Trial Protocol GFR GM-CSF GGT GP GPOH HR IB ICF ICH IMP INR INRC INRG INSS IRF ISF IT ITCC IV MGMT MIBG MHRA MRD MRI MSKCC MTD MYCN NANT NCI NCS NR OS OTC PCP PD PFS PHOX2B PI PIS PK PMA PRES PO PPTP PR REC RECIST RNA GLOMERULAR FILTRATION RATE GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR GAMMA-GLUTAMYL TRANSPEPTIDASE GENERAL PRACTITIONER GERMAN SOCIETY FOR PAEDIATRIC ONCOLOGY & HAEMATOLOGY HEART RATE INVESTIGATOR BROCHURE INFORMED CONSENT FORM INTERNATIONAL CONFERENCE ON HARMONISATION INVESTIGATIONAL MEDICINAL PRODUCT INTERNATIONAL NORMALISED RATIO INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA INTERNATIONAL NEUROBLASTOMA RISK GROUP INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM INSTITUTIONAL REVIEW BOARD INVESTIGATOR SITE FILE IRINOTECAN + TEMOZOLOMIDE ARM INNOVATIVE THERAPIES FOR CHILDREN WITH CANCER INTRAVENOUS O6-METHYGUANINE METHYLTRANSFERASE META-IODO-BENZYL-GUANIDINE MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY MINIMAL RESIDUAL DISEASE MAGNETIC RESONANCE IMAGING MEMORIAL SLOAN KETTERING CANCER CENTRE MAXIMUM TOLERATED DOSE MYELOCYTOMATOSIS VIRAL RELATED ONCOGENE NEW AGENTS FOR NEUROBLASTOMA THERAPY NATIONAL COORDINATING INVESTIGATOR NATIONAL CO-SPONSOR NO RESPONSE OVERALL SURVIVAL OVER THE COUNTER PNEUMOCYSTIS CARNI PNEUMONITIS PROGRESSSIVE DISEASE PROGRESSION FREE SURVIVAL PAIRED-LIKE HOMEOBOX2B PRINCIPAL INVESTIGATOR PATIENT INFORMATION SHEET PHARMACOKINETICS POPULATION-MODELLING ANALYSIS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME ORALLY PAEDIATRIC PRECLINICAL TESTING PROGRAM PARTIAL RESPONSE RESEARCH ETHICS COMMITTEE RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS RIBONUCLEIC ACID BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 15 of 157 BEACON-Neuroblastoma Trial Protocol RTKI RT-qPCR SAE SAR SCT SD SFOP SIOPEN SNP SPC SUSAR SWFI T TH TMA TMG TSC TTo TVD UAR UKCCSG ULN VTE VEGF VGPR WMA RECEPTOR TYROSINE KINASE INHIBITORS REVERSE TRANSCRIPTASE QUANTITATIVE POLYMERASE CHAIN REACTION SERIOUS ADVERSE EVENT SERIOUS ADVERSE REACTION STEM CELL TRANSPLANT STABLE DISEASE FRENCH SOCIETY OF PAEDIATRIC ONCOLOGY INTERNATIONAL SOCIETY PAEDIATRIC ONCOLOGY EUROPEAN NEUROBLASTOMA GROUP SINGLE NUCLEOTIDE POLYMORPHISM SUMMARY OF PRODUCT CHARACTERISTICS SUSPECTED UNEXPECTED SEVERE ADVERSE REACTION STERILE WATER FOR INJECTION TEMOZOLOMIDE ARM TYROSINE HYDROXYLASE TISSUE MICROARRAY TRIAL MANAGEMENT GROUP TRIAL STEERING COMMITTEE TEMOZOLOMIDE + TOPOTECAN ARM TOPOTECAN, VINCRISTINE & DOXORUBICIN UNEXPECTED ADVERSE REACTION UNITED KINGDOM CHILDREN’S CANCER STUDY GROUP UPPER LIMIT OF NORMAL VENOUS THROMBO-EMBOLISM VASCULAR ENDOTHELIAL GROWTH FACTOR VERY GOOD PARTIAL RESPONSE WORLD MEDICAL ASSOCIATION FORMULAE Mosteller formula: BSA (m²) = BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 16 of 157 BEACON-Neuroblastoma Trial Protocol Table of Contents Trial Synopsis ...................................................................................................................................... 12 Title .................................................................................................................................................... 12 Trial Design ........................................................................................................................................ 12 Objectives .......................................................................................................................................... 12 Outcome Measures............................................................................................................................ 12 Patient Population .............................................................................................................................. 13 Sample Size ....................................................................................................................................... 13 Trial Duration...................................................................................................................................... 13 Abbreviations ..................................................................................................................................... 14 1. Background and Rationale ............................................................................................................. 22 1.1 Background............................................................................................................................ 22 1.1.1 Background for the dinutuximab beta amendment............................................................ 28 1.2 Trial Rational.......................................................................................................................... 29 1.2.1 Justification for design ....................................................................................................... 29 1.2.2 Rationale for patient population ......................................................................................... 30 1.2.3 Benefit-risk assessment .................................................................................................... 31 1.2.4 Rationale for the selected backbone schedules: Temozolomide, irinotecan + temozolomide and temozolomide + topotecan .............................................................................. 31 1.2.5 Rationale for dosing schedule of bevacizumab................................................................. 32 1.2.6 Rationale for evaluating chemo-immunotherapy in the BEACON-Neuroblastoma Trial... 32 1.2.7 Rationale for dosing schedule of dinutuximab beta........................................................... 33 1.2.8 Rationale for the use of biomarker studies ........................................................................ 34 1.3 Relevance and future importance ......................................................................................... 35 2. Objectives and Outcome Measures ............................................................................................. 36 2.1 Objectives .............................................................................................................................. 36 2.2 Outcome Measures ............................................................................................................... 37 3. Trial Design ..................................................................................................................................... 37 3.1 Randomisation....................................................................................................................... 37 3.2 Duration of treatment............................................................................................................. 38 3.3 Frequency and duration of follow-up ..................................................................................... 38 4. Eligibility.......................................................................................................................................... 39 4.1 Lifestyle guidelines ................................................................................................................ 39 5. Schedule of activities..................................................................................................................... 39 6. Screening and Consent ................................................................................................................. 40 6.1 Informed Consent .................................................................................................................. 40 6.2 Screening............................................................................................................................... 41 7. Trial Entry........................................................................................................................................ 42 7.1 Procedure for online patient randomisation........................................................................... 42 7.2 Emergency Randomisation ................................................................................................... 42 8. Treatment Details ........................................................................................................................... 43 8.1 Definition of Investigational Medicinal Products (IMPs) ........................................................ 43 9. Bevacizumab randomisation......................................................................................................... 43 9.1 Eligibility criteria for the bevacizumab randomisation............................................................ 43 9.1.1 Inclusion criteria for the bevacizumab randomisation ....................................................... 43 9.1.2 Exclusion criteria for the bevacizumab randomisation ...................................................... 44 9.2 Schedule of activities for the bevacizumab randomisation ................................................... 45 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 17 of 157 BEACON-Neuroblastoma Trial Protocol 9.3 Trial Therapy (bevacizumab randomisation) ......................................................................... 49 9.3.1 Bevacizumab randomisation trial treatment ...................................................................... 49 9.4 Treatment Schedule..................................................................................................................... 51 9.4.1 Day 1 of Cycle 1 ................................................................................................................ 51 9.4.2 Day 1 of subsequent cycles............................................................................................... 51 9.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12) ........................................................ 52 9.4.4 End of Treatment ............................................................................................................... 52 9.4.5 Treatment Duration............................................................................................................ 52 9.5 Dose Modifications for the bevacizumab randomisation ....................................................... 53 9.5.1 Dose Modifications for AEs due to chemotherapy - for the bevacizumab randomisation. 56 9.5.2 Bevacizumab – Infusion-related Reaction/Infusional Site Extravasation Management Guidelines ...................................................................................................................................... 62 9.5.3 Bevacizumab - Treatment Delays ..................................................................................... 63 9.5.4 Bevacizumab - Discontinuation ........................................................................................ 64 9.5.5 Bevacizumab - Toxicity Management guidelines .............................................................. 65 9.6 Central Venous Access Device (CVAD)................................................................................ 67 10 Dinutuximab beta and topotecan randomisations...................................................................... 68 10.1 Eligibility for the dinutuximab beta randomisation ................................................................. 68 10.1.1 Inclusion criteria for the dinutuximab beta randomisation ............................................. 68 10.1.2 Exclusion criteria for the dinutuximab beta randomisation ............................................ 69 10.2 Schedule of events for the dinutuximab beta and topotecan randomisations....................... 70 10.3 Trial therapy (dinutuximab beta and topotecan randomisations) .......................................... 74 10.3.1 Dinutuximab beta and topotecan trial treatment................................................................ 75 10.4 Treatment Schedule .............................................................................................................. 76 10.4.1 Day 1 of Cycle 1 ............................................................................................................ 76 10.4.2 Day 1 of subsequent cycles........................................................................................... 76 10.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12 on chemotherapy only) ............... 77 10.4.4 End of Treatment ........................................................................................................... 77 10.4.5 Treatment Duration............................................................................................................ 78 10.4.6 Cross-over ......................................................................................................................... 78 10.5 Dose Modifications – dinutuximab beta and topotecan randomisations ............................... 79 10.5.1 Dose modifications for dinutuximab beta specific toxicities .......................................... 79 10.5.2 Dose modifications for haematological toxicity.............................................................. 81 10.5.3 Dose modifications for hepatic toxicity .......................................................................... 82 11 Treatment Compliance................................................................................................................... 84 12 Supportive Treatment .................................................................................................................... 84 12.1 Nausea and Vomiting ............................................................................................................ 84 12.2 Growth Factors ...................................................................................................................... 84 12.3 Fever and neutropenia .......................................................................................................... 84 12.4 Blood products....................................................................................................................... 84 12.5 Pneumocystis jirovecii pneumonia (PJP) prophylaxis ........................................................... 84 12.6 Management of side effects caused by non-selective NSAIDs as cyclooxygenase (COX) type I and II inhibitors ......................................................................................................................... 84 12.7 Supportive care during Dinutuximab beta infusion................................................................ 85 12.7.1 Pain Management.......................................................................................................... 85 12.7.2 Prevention of dinutuximab beta related infusion reactions............................................ 86 13 Concomitant Medication................................................................................................................ 87 14 Assessments .................................................................................................................................. 87 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 18 of 157 BEACON-Neuroblastoma Trial Protocol 14.1 Response assessment .......................................................................................................... 88 15 Biomarkers...................................................................................................................................... 88 15.1 Blood sampling safety ........................................................................................................... 88 15.2 MRI-derived functional imaging biomarkers of angiogenesis................................................ 90 15.3 Molecular monitoring mRNA.................................................................................................. 90 15.4 Neuroblastoma exploratory biomarker analyses ................................................................... 90 15.5 Sample Collection.................................................................................................................. 92 15.5.1 Peripheral blood samples .............................................................................................. 92 15.5.2 Bone Marrow Samples .................................................................................................. 92 15.5.3 Archival tumour samples ............................................................................................... 92 16 Patient Follow Up ........................................................................................................................... 93 16.1 Patient Withdrawal................................................................................................................. 93 17 Pharmaceutical Information .......................................................................................................... 94 17.1 Definition of Investigational Medicinal Product ...................................................................... 94 17.2 Bevacizumab ......................................................................................................................... 94 17.2.1 Bevacizumab - Drug Supply .......................................................................................... 94 17.2.2 Bevacizumab - Ordering ............................................................................................... 94 17.2.3 Bevacizumab - Formulation, Packaging and Labelling ................................................. 94 17.2.4 Bevacizumab - Preparation and Dispensing ................................................................. 95 17.2.5 Compatibility information ............................................................................................... 95 17.2.6 Bevacizumab - Administration ....................................................................................... 95 17.2.7 Bevacizumab – Accountability....................................................................................... 96 17.2.8 Bevacizumab - Destruction............................................................................................ 96 17.3 Cyclophosphamide ................................................................................................................ 96 17.4 Dinutuximab beta................................................................................................................... 96 17.5 Irinotecan ............................................................................................................................... 96 17.5.1 Irinotecan - Drug Supply ............................................................................................... 96 17.5.2 Irinotecan - Formulation, Packaging and Labelling ....................................................... 96 17.5.3 Irinotecan - Preparation and Dispensing ....................................................................... 97 17.5.4 Compatibility information ............................................................................................... 97 17.5.5 Irinotecan - Administration ............................................................................................. 97 17.6 Temozolomide ....................................................................................................................... 97 17.6.1 Temozolomide – Drug Supply ....................................................................................... 97 17.6.2 Temozolomide - Formulation, Packaging and Labelling ............................................... 97 17.6.3 Temozolomide - Administration ..................................................................................... 97 17.7 Topotecan.............................................................................................................................. 98 17.7.1 Topotecan - Drug Supply.............................................................................................. 98 17.7.2 Topotecan - Formulation, Packaging and Labelling ..................................................... 98 17.7.3 Topotecan - Preparation and Dispensing ..................................................................... 98 17.7.4 Topotecan - Compatibility information ........................................................................... 98 17.7.5 Topotecan - Administration........................................................................................... 99 18 Adverse Event Reporting .............................................................................................................. 99 18.1 Reporting Requirements........................................................................................................ 99 18.1.1 Adverse Events (AE) ..................................................................................................... 99 18.1.2 AESIs of Bevacizumab .................................................................................................. 99 18.1.3 Serious Adverse Advents (SAE).................................................................................... 99 18.1.4 Reporting period .......................................................................................................... 100 18.2 Reporting Procedure ........................................................................................................... 100 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 19 of 157 BEACON-Neuroblastoma Trial Protocol 18.2.1 Site............................................................................................................................... 100 18.2.2 Trial Office ................................................................................................................... 102 18.2.3 Reporting to the Competent Authority and main Research Ethics Committee ........... 102 18.2.4 Investigators ................................................................................................................ 102 18.2.5 Data Monitoring Committee ......................................................................................... 102 18.2.6 Manufacturer of Investigational Medicinal Product...................................................... 102 19 Data Handling and Record Keeping ........................................................................................... 103 19.1 Data Collection .................................................................................................................... 103 19.2 Archiving .............................................................................................................................. 103 20 Quality Management .................................................................................................................... 103 20.1 Site Set-up and Initiation ..................................................................................................... 103 20.2 On-site Monitoring ............................................................................................................... 104 20.3 Central Monitoring ............................................................................................................... 104 20.4 Audit and Inspection ............................................................................................................ 104 20.5 Notification of Serious Breaches ......................................................................................... 104 21 End of Trial Definition .................................................................................................................. 105 22 Statistical Considerations ........................................................................................................... 105 22.1 Trial Design.......................................................................................................................... 105 22.2 Definition of Outcome Measures ......................................................................................... 106 22.2.1 Primary ........................................................................................................................ 106 22.2.2 Secondary.................................................................................................................... 106 22.2.3 Exploratory/Tertiary ..................................................................................................... 106 22.3 Sample Size......................................................................................................................... 106 22.4 Interim and Main Analyses of Outcome Measures.............................................................. 108 22.4.1 Planned Interim Analyses ............................................................................................ 108 22.4.2 Main Analysis............................................................................................................... 108 22.5 Stopping Guidelines ............................................................................................................ 110 23 Trial Organisational Structure..................................................................................................... 110 23.1 Coordinating Sponsor .......................................................................................................... 110 23.2 Co-Sponsor Centres ........................................................................................................... 110 23.3 Relationship of trial committees........................................................................................... 112 23.4 Trial Management Group..................................................................................................... 112 23.5 Trial Steering Committee ..................................................................................................... 112 23.6 Data Monitoring Committee................................................................................................. 112 23.7 Finance ................................................................................................................................ 113 23.8 NIHR CRN Portfolio ............................................................................................................. 113 24 Ethical Considerations ................................................................................................................ 113 25 Confidentiality and Data Protection ........................................................................................... 114 26 Insurance and Indemnity ............................................................................................................. 115 27 Publication Policy ........................................................................................................................ 116 28 Reference List............................................................................................................................... 117 Appendix 1 – WMA Declaration of Helsinki .................................................................................... 124 Appendix 2 - Definition of Adverse Events ..................................................................................... 127 Appendix 3 - Common Toxicity Criteria Grading ........................................................................... 129 Appendix 4 – RECIST Criteria 1.1 .................................................................................................... 130 Appendix 5 – Tumor Response at Metastatic Soft Tissue and Bone Sites (Park et al. 2017) ... 133 Appendix 6 - CURIE & SIOPEN scoring methods for neuroblastoma ......................................... 134 Appendix 7 – Temozolomide Dosing............................................................................................... 136 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 20 of 157 BEACON-Neuroblastoma Trial Protocol Appendix 8 – Blood Pressure Levels by Age and Height Percentile for Children and Adolescents ....................................................................................................................................... 139 Appendix 9 – Height for Age Chart - Girls ...................................................................................... 144 Appendix 10 – Height for Age Chart - Boys.................................................................................... 149 Appendix 11 – Lansky and Karnofsky/ECOG Scales .................................................................... 154 Appendix 12 – Tanner Staging ......................................................................................................... 156 Appendix 13 – Clinical studies of anti-GD2 therapies in combination with chemotherapy ...... 157 LIST OF TABLES Table 1 - Second line chemotherapy regimens tested in phase II in relapsed or refractory neuroblastoma since 2000 ..........
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