pembrolizumab · 2016-11-29 · pembrolizumab administration •can be administered through a...
TRANSCRIPT
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Pembrolizumab
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Overview
• A Phase II trial of MK-3475 (Pembrolizumab) in children’s solid
tumours and lymphoma
• Chemotherapy used to treat advanced melanoma or
advanced/relapsed/refractory PD-L1 positive malignant solid tumours
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Eligibility
• Aged 6 months to 18 years of age
• Advanced melanoma or relapsed/refractory PD-L1 positive malignant solid
tumour or lymphoma
• Malignancy that is incurable and has either failed prior therapy, there is no
standard therapy or the standard therapy isn’t considered appropriate
• Be willing and informed to sign consent to the study
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Exclusion Criteria
• Had prior chemotherapy or radiation <2 weeks
prior to starting Pembrolizumab
• Has a known additional malignancy that’s
progressing or requires treatment e.g. basal cell
carcinoma
• Has known active CNS metastases or disease
• Interstitial lung disease or active infection
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What is PD-1?
• Two main types of T-cells (T-lymphocytes): Helper and Cytotoxic
*Cytotoxic: destroy tumour/cancer cells, virally infected cells or cells damaged in another way
*Helper T-cells: once activated, secrete small proteins (cytokines) that assist in the active immune response
• PD-1 is an immune inhibitory receptor present on several immune cells, particularly cytotoxic T cells.
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What is PD-L1?
• PD-L1 is a ligand (binding molecule which produces a signal) present on tumour cells
• A receptor normally responsible for inhibiting the immune response to cancer cells
• Normally, PD-L1 binds to the receptor PD-1 to modulate activation or inhibition
• This effect is normally necessary to avoid inappropriate overreactions, e.g. autoimmune disease in healthy individuals
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Pembrolizumab
• A highly selective mAb designed to block the interaction between PD-1 and PD-L1.
• Blocks the inhibitory ligand of PD-1
• In cancer patients, the blocking against this receptor reinvigorates the immune system, allowing it to target and destroy cancer cells
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Rationale
• High levels of PD-L1 on tumour cells have been found to correlate with
poor prognosis and survival in various cancer types
• This suggests that the PD-1/PD-L1 pathway plays a critical role in tumour
evasion and is thus an attractive target for therapeutic intervention.
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Who are we treating?
• Four target tumour cohorts: neuroblastoma, osteosarcoma, Ewings
sarcoma/peripheral PNET and Hodgkins lymphoma
• Other cohorts of interest: Wilms, hepatoblastoma, non-Hodgkin lymphoma,
non-/rhabdomyosarcoma and melanomas.
• Advanced/relapsed/refractory (except melanoma)
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Pembrolizumab Administration
• Delivered in a 3-week cycle, on Day 1 of each Cycle
• Dose: 2mg/kg (starting dose)
• Can be administered with +/- 10% of weight used for advanced dose calculation
• Route: IV infusion
• Time: 30 minute infusion (N. Saline flush pre and post)
• Dose of 50mg or above: IV bag with infusion set
• Doses of <50 mg infused via syringe pump
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Pembrolizumab Administration
• Can be administered through a central or peripheral line
• Can be administered +/- 3 days of Day 1 of Cycle
• Outpatient basis
• Nurses must wear PPEs (protective gown, eyewear, closed-toe shoes and chemo gloves) at all times throughout the administration
• Do not co-administer drugs through the same line
• Depending on pharmacokinetic response to Pembrolizumab, dose alterations may increase to a max of 10mg/kg Q2W
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Monitoring
• Vital Signs (BP, HR, Sa02, Temp and RR) and Height/Weight need to be recorded:
-Pre-screening
-Pre-treatment Day 1 of each Cycle
-30 days post Final visit
• Physical Exam performed on Cycle 1, Day 1, 8 & 15 and Pre-treatment Day 1 of each Cycle (all can be completed in DOU)
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PK bloods
• Pharmacokinetic bloods are taken on this trial:
• Cycle 1, Day 1: pre and post-dose
• Day 4-8: post D1 administration of dose
• Day 15: post D1 administration of dose
• Cycle 2 & 4, Day 1: Pre-dose
• Cycle 8, Day 1: pre and post-dose
• Every 4 Cycles after Cycle 8 (12, 16…): Day 1, pre-dose
• (Bloods should be taken from opposite arm to administration…if possible!)
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Toxicities and Nursing Management
• Pembrolizumab is generally well tolerated
• Immunomodulatory agent, therefore immune-mediated adverse events are of primary concern;
• Pneumonitis
• Colitis
• Hepatitis
• Hypophysitis (inflammation of the pituitary gland)
• Hyper/hypothyroidism
• Nephritis
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One of the most common adverse events?
Pneumonitis
Test-how do we monitor for Pneumonitis?
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Pneumonitis: What to monitor for…
• Nursing Monitoring:
• SaO2
• RR
• WOB
• Dyspnoea
• Non-productive cough
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Toxicities & Nursing Management
• Other adverse effects include:
• Fatigue
• Rash
• Vitiligo (chronic skin condition-portions of skin lose pigment)
• Arthralgia
• Cough
• Decreased Appetite
• Headache
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Infusion Reactions Guidelines
• Any signs and symptoms (if any) will usually develop within short time of infusion commencing
• Infusion Reaction guidelines in Nursing Fast Facts on
ward/in DOU
• Dependent on grade/severity of event
• Stop infusion and monitor symptoms
• IV fluids, antihistamines & NSAIDs/corticosteroids
• Increase monitoring of vital signs
• (Please report to Dr. and Clinical Trials team! )
• Drug can only last 4 hours once out of fridge
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Toxicities and Nursing Management
• Patients experiencing toxicities will have infusion delayed until toxicities have resolved to grade 1 or baseline.
• When symptoms improve to a grade 1 or less level, (if on corticosteroids) corticosteroid treatment should begin to taper and last no longer than 4 weeks
• Those who develop symptoms of grade 2 toxicities (i.e requiring antihistamines, NSAIDS, IV fluids) DESPITE pre-medication should be discontinued from the trial
• Those who develop symptoms of grade 3 toxicities (i.e symptoms that prolong hospitalisation or are considered life-threatening) should be discontinued from the trial
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Questions
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Thank you
Any questions please call!
Early Phase Study Coordinator:
Ryan Hehir
#9345 6214
Research Nurse:
Gemma Rowan
#9345 6845
#6845
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References
• MK 3475 Protocol/Amendment No: 051-02 ‘A Phase I/II Study of Pembrolizumab (MK-3475) in Children with Advanced Melanoma or a PD-L1 Positive Advanced, Relapsed or Refractory Solid Tumour of Lymphoma (KEYNOTE-051)’ Version 2.0, 2015
• MK 3475 Pharmacy Manual, MERCK Sharp & Dohme, Corporation, Version 1.0, 2015
• Cancer Research Institute 2015, ‘Checkpoint Inhibitors: Taking the Brakes off the Immune System’ retrieved online https://www.youtube.com/watch?v=v9NBUeU3PG0
• Royal Children’s Hospital 2016, ‘Pneumonia: Clinical Practice Guidelines’, Royal Children’s Hospital, retrieved online http://www.rch.org.au/clinicalguide/guideline_index/Pneumonia_Guideline/