Pembrolizumab

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

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

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

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.

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

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

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.

https://www.youtube.com/watch?v=v9N

BUeU3PG0

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)

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

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

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)

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!)

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

One of the most common adverse events?

Pneumonitis

Test-how do we monitor for Pneumonitis?

Pneumonitis: What to monitor for…

• Nursing Monitoring:

• SaO2

• RR

• WOB

• Dyspnoea

• Non-productive cough

Toxicities & Nursing Management

• Other adverse effects include:

• Fatigue

• Rash

• Vitiligo (chronic skin condition-portions of skin lose pigment)

• Arthralgia

• Cough

• Decreased Appetite

• Headache

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

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

Questions

Thank you

Any questions please call!

Early Phase Study Coordinator:

Ryan Hehir

#9345 6214

Research Nurse:

Gemma Rowan

#9345 6845

#6845

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/