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Systemic Anti Cancer Treatment Protocol

TCHP
Docetaxel, Carboplatin, Trastuzumab, Pertuzumab
Neoadjuvant and Adjuvant Protocol

PROTOCOL REF: MPHATCHP

(Version No: 2.2)

During COVID19 there are contingency options for pertuzumab/trastuzumab

combination to be administered without chemotherapy, please see blueteq for full
criteria and register patient at time of consent to ensure compliance with rapidly
changing criteria.

Switch from docetaxel to weekly paclitaxel is permitted

Approved for use in:

Neoadjuvant treatment: first line treatment of HER2 positive T2 to T4b and/or
histologically or cytologically proven node positive early breast cancer.
Baseline LVEF ≥ 55%

Adjuvant treatment: following neoadjuvant treatment (as detailed) and ONLY if fulfills
one of the following criteria:
 Axillary lymph node (LN) involvement pathologically confirmed prior to the start of
neoadjuvant chemotherapy.
 Node negative prior to neoadjuvant treatment:
o Confirmed residual carcinoma in the axillary node(s) following surgery.
o In the absence of invasive carcinoma in the axillary LNs post-surgery,
confirmed histological changes (e.g. fibrosis) indicative of previous axillary
nodal involvement.

No disease progression following neoadjuvant treatment.

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Prior to starting adjuvant treatment- LVEF ≥ 50%.

PS 0-1

Separate Blueteq registration forms required for neoadjuvant and adjuvant use.

Preparation of Phesgo:
Loading Dose (Pertuzumab/Trastzumab S/C 1200mg/600mg)

Withdrawn the contents of the vial into a 15mL syringe using a transfer needle and then
change the needle to a subcutaneous 25-27 Gauge needle prior to administering the
dose

Maintenance Dose (Pertuzumab/Trastzumab S/C 600mg/600mg)

Withdrawn the contents of the vial into a 10mL syringe using a transfer needle and then
change the needle to a subcutaneous 25-27 Gauge needle prior to administering the
dose

Considerations
 The injection site should be alternated between the left and right thigh.
 Ensure both nursing staff and patient are in comfortable position before
beginning
 New injections should be given at least 2.5 cm from the old site and never into
areas where the skin is red, bruised, tender, or hard.
 Medication should be warmed/come to room temperature before injection. This is
easily done by asking patient to hold vial of Phesgo while nurse performs
assessment/documentation. Never injection cold medication into the patient
 The dose should not be split between two syringes or between two sites of
administration

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Dosage:
Neoadjuvant treatment:
Drug Dosage Route Frequency

Cycles 1 to 6
Carboplatin* AUC 5 or 6 IV infusion Day 1 only of a
21 day cycle

Cycles 1 to 6
Docetaxel 75mg/m2 IV infusion Day 1 only of a
21 day cycle

OR
Cycles 1 to 6
Paclitaxel 80mg/m2 IV infusion Days 1, 8 and 15
of a 21 day cycle

Pertuzumab 1200mg/ Subcutaneous Cycle 1 loading

Phesgo
Trastuzumab 600mg injection dose

Pertuzumab 600mg/ Subcutaneous

Phesgo Cycles 2 to 6
Trastuzumab 600mg injection

Alternative intravenous option

Drug Dosage Route Frequency

8mg/kg loading dose cycle 1

Trastuzumab then 6mg/kg cycles 2 to 6 IV infusion Cycles 1 to 6
Day 1 only of a
21 day cycle
840mg loading dose cycle 1
Pertuzumab IV infusion
then 420mg cycles 2 to 6

*Carboplatin Dosing
Meditech calculates creatinine clearance using the Wright formula and therefore
creatinine clearance will need to be entered manually to use Cockroft and Gault
formula (applications for calculating creatinine using both formulas are available
on the Remote Citrix Web Portal).
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Calvert formula for Carboplatin dosage-:

Carboplatin dose in mg = AUC x (GFR or CrCl + 25)

Use area under the curve (AUC) 5 for GFR calculations using Wright formula and
AUC 6 when using Creatinine Clearance (CrCl) using Cockroft and Gault formula. This
formula will then need to be used throughout the course of carboplatin treatment.

If estimated GFR is used the Wright formula must be used for creatinine clearance.

In both cases carboplatin dose will be capped at 890mg.

Adjuvant treatment:
As 18 cycles of HER2 agents will be administered, ensure that cycle numbers are
correct when starting adjuvant treatment to avoid stopping sooner than planned.

Eligible for adjuvant treatment with Pertuzumab

Drug Dosage Route Frequency

Pertuzumab 1200mg/ Subcutaneous Loading dose
Phesgo
Trastuzumab 600mg injection required if 6
weeks from
previous dose
Pertuzumab 600mg/ Subcutaneous
Phesgo Cycles 7 to 18
Trastuzumab 600mg injection
Day 1 only of a
21 day cycle

Intravenous alternative

Drug Dosage Route Frequency

8mg/kg loading dose (≥ 6
Cycles 7 to 18
weeks from last dose) cycle 8.
Day 1 only of a 21
Trastuzumab Then 6mg/kg to continue IV infusion
day cycle
thereafter for a total of 18
doses

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840mg loading dose (≥ 6

weeks from last dose) cycle 8.
Pertuzumab IV infusion
Then 420mg thereafter for a
total of 18 doses

Not eligible for adjuvant treatment with Pertuzumab:

Drug Dose Route Frequency

600mg
Cycles 7 to 18
Trastuzumab To continue for SC
Day 1 only of a 21 day cycle
18 doses in total

Supportive Treatments:
Premedication of dexamethasone 8 mg oral twice daily for 3 days starting 1 day prior to
docetaxel administration to prevent hypersensitivity reactions.
Ondansetron 16mg PO or 8mg IV day 1 of treatment.
Domperidone 10mg tablets orally three times a day when required
Filgrastim subcutaneous injection daily for 7 days starting on day 3, dose as follows:
 Weight < 70kg- Filgrastim 300 micrograms daily SC.
 Weight ≥ 70kg- Filgrastim 480 micrograms daily SC.

Extravasation Risk:
Refer to the network guidance for the prevention and management of
extravasation.
Docetaxel – exfoliant
Carboplatin – irritant
Trastuzumab – neutral
Pertuzumab – neutral
Paclitaxel- vesicant
Phesgo- No extravasation risk as subcutaneous route of injection

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Administration:
Cycle 1

Carboplatin, Docetaxel and subcutaneous Trastuzumab/Pertuzumab

Day Drug Dose Route Diluent and rate

Dexamethasone* 8 mg twice daily for 3 days starting 1 day prior to docetaxel

1 30 minutes before
Ondansetron 16mg PO
chemotherapy

Pertuzumab
1200mg/ S/C
Phesgo Over 8 minutes
trastuzumab injection
600mg

250mL 0.9% sodium chloride

Docetaxel 75mg/m2 IV
over 60 minutes
500mL glucose 5% over 60
Carboplatin AUC 5 or 6 IV
minutes

Carboplatin, Docetaxel, Trastuzumab, Pertuzumab intravenous

Day Drug Dose Route Diluent and rate

Dexamethasone* 8 mg twice daily for 3 days starting 1 day prior to docetaxel

1
Ondansetron 16mg PO 30 minutes before chemotherapy
840mg
250mL sodium chloride 0.9%
Pertuzumab Loading IV
over 60 minutes
Dose
8mg/kg
250mL sodium chloride 0.9%
Trastuzumab Loading IV
over 90 minutes
Dose
250mL 0.9% sodium chloride
Docetaxel 75mg/m2 IV
over 60 minutes
500mL glucose 5% over 60
Carboplatin AUC 5 or 6 IV
minutes

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*If oral dexamethasone has not been taken then an intravenous dose of 8mg can be
administered on the day of treatment, in addition to the oral dose of 8mg

OR

Paclitaxel, Carboplatin and subcutaneous Trastuzumab/Pertuzumab

Day Drug Dose Route Diluent and rate

30 minutes before
Ondansetron 16mg PO
chemotherapy

Pertuzumab
1200mg/ S/C
Phesgo Over 8 minutes
trastuzumab injection
600mg

30 minutes before
Dexamethasone 6.6mg IV Bolus chemotherapy
Reduce to 3.3mg from week 2

1 30 minutes before
Chlorphenamine 10mg IV Bolus
chemotherapy
At least 1 hour before
Famotidine 20mg Orally
chemotherapy
250 to 500mL sodium chloride
0.9% over 60 minutes
Paclitaxel 80mg/m2 IV infusion using a non-PVC giving set with
a 0.22 micron filter

500mL glucose 5% over 60

Carboplatin AUC 5 or 6 IV
minutes

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Paclitaxel, Carboplatin,Trastuzumab, Pertuzumab intravenous

Day Drug Dose Route Diluent and rate

1
Ondansetron 16mg PO 30 minutes before chemotherapy
840mg
250mL sodium chloride 0.9%
Pertuzumab Loading IV
over 60 minutes
Dose
8mg/kg
250mL sodium chloride 0.9%
Trastuzumab Loading IV
over 90 minutes
Dose
IV 30 minutes before chemotherapy
Dexamethasone 6.6mg
Bolus Reduce to 3.3mg from week 2
IV
Chlorphenamine 10mg 30 minutes before chemotherapy
Bolus
At least 1 hour before
Famotidine 20mg orally
chemotherapy
250 to 500mL sodium chloride
IV 0.9% over 60 minutes
Paclitaxel 80mg/m2
infusion using a non-PVC giving set with
a 0.22 micron filter
500mL glucose 5% over 60
Carboplatin AUC 5 or 6 IV
minutes

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Cycle 2 to 6

Carboplatin, Docetaxel and subcutaneous Trastuzumab/Pertuzumab

Day Drug Dose Route Diluent and rate

Dexamethasone* 8 mg twice daily for 3 days starting 1 day prior to docetaxel

1 30 minutes before
Ondansetron 16mg PO
chemotherapy

Pertuzumab
600mg/ S/C
Phesgo Over 5 minutes
trastuzumab injection
600mg

250mL 0.9% sodium chloride

Docetaxel 75mg/m2 IV
over 60 minutes
500mL glucose 5% over 60
Carboplatin AUC 5 or 6 IV
minutes

Carboplatin, Docetaxel, Trastuzumab, Pertuzumab intravenous

Day Drug Dose Route Diluent and rate

Dexamethasone* 8 mg twice daily for 3 days starting 1 day prior to docetaxel

1
Ondansetron 16mg PO 30 minutes before chemotherapy
420mg
250mL sodium chloride 0.9%
Pertuzumab Maintenance IV
over 30 minutes
Dose
6mg/kg 250mL sodium chloride 0.9%
Trastuzumab Maintenance IV over 60 minutes at cycle 2 then
Dose over 30 minutes if tolerated
250mL 0.9% sodium chloride
Docetaxel 75mg/m2 IV
over 60 minutes
500mL glucose 5% over 60
Carboplatin AUC 5 or 6 IV
minutes

*If oral dexamethasone has not been taken then an intravenous dose of 8mg can be
administered on the day of treatment, in addition to the oral dose of 8mg

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OR

Paclitaxel, Carboplatin and subcutaneous Trastuzumab/Pertuzumab

Day Drug Dose Route Diluent and rate

30 minutes before
Ondansetron 16mg PO
chemotherapy
1
Pertuzumab
600mg/ S/C
Phesgo Over 5 minutes
trastuzumab injection
600mg

30 minutes before
Dexamethasone 6.6mg IV Bolus chemotherapy
Reduce to 3.3mg from week 2
30 minutes before
Chlorphenamine 10mg IV Bolus
chemotherapy
1,8
And At least 1 hour before
15 Famotidine 20mg Orally chemotherapy for the first 3
doses
250 to 500mL sodium chloride
0.9% over 60 minutes
Paclitaxel 80mg/m2 IV infusion using a non-PVC giving set with
a 0.22 micron filter

500mL glucose 5% over 60

1 Carboplatin AUC 5 or 6 IV
minutes

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Paclitaxel, Carboplatin,Trastuzumab, Pertuzumab intravenous

Day Drug Dose Route Diluent and rate

Ondansetron 16mg PO 30 minutes before chemotherapy

840mg
1 250mL sodium chloride 0.9%
Pertuzumab Loading IV
over 60 minutes
Dose
8mg/kg
250mL sodium chloride 0.9%
Trastuzumab Loading IV
over 90 minutes
Dose
IV 30 minutes before chemotherapy
Dexamethasone 6.6mg
Bolus Reduce to 3.3mg from week 2
At least 1 hour before
Famotidine 20mg orally
chemotherapy
1,8
and IV
Chlorphenamine 10mg 30 minutes before chemotherapy
15 Bolus
250 to 500mL sodium chloride
IV 0.9% over 60 minutes
Paclitaxel 80mg/m2
infusion using a non-PVC giving set with
a 0.22 micron filter
500mL glucose 5% over 60
1 Carboplatin AUC 5 or 6 IV
minutes

Cycle 7 to 18
To commence 3 weeks after final cycle of chemotherapy (cycle 7 may be before surgery
has taken place).

Adjuvant pertuzumab treatment

Subcutaneous

Drug Dosage Route Frequency

Over 8 minutes

Pertuzumab 1200mg/ Subcutaneous Loading dose required

Phesgo ONLY if 6 weeks from
Trastuzumab 600mg injection
previous dose

Pertuzumab 600mg/ Subcutaneous Over 5 minutes

Phesgo
Trastuzumab 600mg injection

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OR

Intravenous

Day Drug Dose Route Diluent and rate

8mg/kg loading
dose (≥ 6 weeks
from last dose) 250mL sodium chloride
cycle 7. 0.9% over 60 minutes. If
Pertuzumab IV infusion well tolerated then
Then 6mg/kg to reduce to 30 minutes on
continue thereafter subsequent infusions.
1
for a total of 18
doses
840mg loading dose
(≥ 6 weeks from last 250mL sodium chloride
dose) cycle 7. 0.9% over 90 minutes. If
Trastuzumab IV infusion well tolerated then
Then 420mg reduce to 30 minutes on
thereafter for a total subsequent infusions.
of 18 doses

OR

Adjuvant trastuzumab treatment ONLY

Day Drug Dose Route Diluent and rate

1 Trastuzumab 600mg SC Over 5 minutes

Cycles repeated every 21 days

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Main Toxicities:
TCH-P
Haematological Neutropenia, thrombocytopenia and anaemia.
Gastrointestinal Nausea, vomiting, stomatitis, diarrhoea, mucositis.

Cardiotoxicity Pertuzumab and Trastuzumab - decreases in LVEF have been

reported with medicinal products that block HER2 activity, including
Pertuzumab and Trastuzumab; see cardiotoxicity dose modification
section below for details.
Dermatological Alopecia, normally reversible, although can be permanent following
docetaxel. Docetaxel: Brittle, chipped and ridged nails
Urological Carboplatin is nephrotoxic.
Ototoxicity Common when carboplatin used in high doses.

Ocular Watery eyes, gritty and irritated. Risk of cortical blindness with
carboplatin; renal impairment is thought to increase this risk.
Hypersensitivity Reactions may occur within a few minutes following the initiation of
reactions treatment with docetaxel, facilities for the treatment of hypotension
and bronchospasm should be available.

If hypersensitivity reactions occur, minor symptoms such as

flushing or localised rash with or without pruritus do not require
interruption of therapy. However, severe reactions, such as severe
hypotension, bronchospasm or generalised rash/erythema require
immediate discontinuation of docetaxel and appropriate treatment.
Patients who have developed severe hypersensitivity reactions
should not be re-challenged with docetaxel.

Patients should be monitored for hypersensitivity and infusion

reactions with Pertuzumab for 60 minutes after the first dose, and
for 30 minutes after subsequent doses.

Trastuzumab: Infusion reactions, allergic-like reactions and

hypersensitivity can occur. The majority of these events occur
during or within 2.5 hours of the start of the first infusion. Should an
infusion reaction occur the infusion should be discontinued or the
rate of infusion slowed and the patient should be monitored until
resolution of all observed symptoms.
Patients experiencing dyspnoea at rest may be at increased risk of
a fatal infusion reaction; these patients should not be treated with
Trastuzumab.
Nervous system Taxanes: peripheral neuropathy is very common
Musculoskeletal Arthralgia, myalgia common with Taxanes.
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Infertility Amenorrhea, risk of premature menopause

However ensure appropriate contraceptive advice is given

Investigations and Treatment Plan:

Cycle Cycle Cycle Cycle Cycle Cycle
Pre Comments
1 2 3 4 5 6
Alternate
cycles
then every 3
Clinical months
X X X X
Assessment whilst on
pertuzumab
and/or
trastuzumab.
SACT
assessment
X X X X X X X Every cycle
(including
toxicities and PS)
ECHO must
be
performed
before
pertuzumab
ECHO / ECG X X and/or
trastuzumab
commences.
Then every 4
months
thereafter
FBC X X X X X X Every cycle
U&E & LFT X X X X X X Every cycle
Calculate
GFR or CrCl* and
check carboplatin
X X X X X X Cycles 1-6
dose using the
carboplatin
calculator.
Informed Consent X
Weight recorded X X X X X X X Every cycle
Height recorded X X

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Dose Modifications and Toxicity Management:

Haematological Toxicity:

Proceed on day 1 if-

Plt ≥ 100 x 109/L ANC ≥ 1.0 x 109/L

Delay 1 week on day 1 if-

Plt ≤ 99 x 109/L ANC ≤ 0.9 x 109/L

Second episode or severe neutropenic sepsis: Defer by 7 days or until blood counts
recovered if Neutrophils < 1.0 or platelets < 100 x 109/L and reduce to 80% dose.

For pertuzumab/trastuzumab only cycles – no blood tests required

Hepatic Impairment:

Docetaxel
AST and/or ALT > 1.5- 5 x ULN concomitant with Consider 75%
ALP > 2.5 –5.0 x ULN and normal bilirubin of the original
dose
AST or ALT >1.5-5 x ULN concomitant with ALP ≤ 2.5-6 x ULN consider 50%
and/or of the original
bilirubin ≤ 1-1.5 x ULN dose
Bilirubin > 1.5 x ULN Not
or recommended
AST/ALT > 10 x ULN
or
ALP > 6 x ULN

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Paclitaxel

Bilirubin less than 1.25 times ULN and Give 100% dose
AST < 10 x ULN

Bilirubin greater than 1.25 times ULN Consider dose reduction

ALP more than 3 times ULN Consider dose reduction

ALT and/or AST ≥10 x ULN or bilirubin Contra-.indicated

> 5 x ULN:

Carboplatin, Trastuzumab and Pertuzumab

No need for dose adjustment is required.

Renal impairment:
Patients with creatinine clearance values of less than 60 mL/min are at greater risk
to develop myelosuppression.

Carboplatin
The optimal use of Carboplatin in patients presenting with impaired renal function
requires adequate dosage adjustments and frequent monitoring of both haematological
nadirs and renal function.

Carboplatin is contraindicated if GFR or CrCl ≤ 20 ml/min. Do not give carboplatin and

discuss with Oncologist.

Trastuzumab, Pertuzumab, Paclitaxel and Docetaxel

All grades including patients on HDx - no dose adjustment required.

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Peripheral Neuropathy
NCI-CTC grade 2 peripheral neuropathy: withhold taxane until neuropathy recovers to
grade 1 then dose reduce by 20%
If NCI-CTC grade 3 (or persistent grade 2) peripheral neuropathy occurs, discontinue
taxane.

Pulmonary Impairment:

Trastuzumab-Pulmonary events have been reported with the use of trastuzumab.

These events have occasionally been fatal.
Caution should be exercised for pneumonitis.

Dose Modifications
Dose reductions for trastuzumab and pertuzumab are not recommended. If trastuzumab
treatment is discontinued, treatment with Pertuzumab should be discontinued.

Recommendations regarding delayed or missed doses of trastuzumab and pertuzumab

Time between two Intravenous pertuzumab subcutaneous
sequential and trastuzumab Phesgo trastuzumab
infusions single agent
< 6 weeks The 420 mg dose of The 600mg/600mg fixed The fixed dose of
intravenous pertuzumab dose should be 600mg
should be administered administered as soon as trastuzumab SC
as soon as possible. Do possible should be
not wait until the next administered as
planned dose. Thereafter, soon as possible.
revert to the original Do not wait until
planned schedule. the next planned
≥ 6 weeks The 840 mg loading dose The loading dose of dose.
of intravenous 1200mg/600mg should
pertuzumab should be re- be administered over 8
administered as a 60 minutes and then back to
minute infusion, followed 600mg/600mg
by a maintenance dose of maintenance dose every
420 mg IV administered 3 weeks thereafter.
every 3 weeks thereafter.

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Toxicities

Hypersensitivity
Taxanes- If hypersensitivity reactions occur; minor symptoms such as flushing or
localised rash with or without pruritus do not require interruption of therapy. However,
severe reactions, such as severe hypotension, bronchospasm or generalised
rash/erythema require immediate discontinuation of taxane and appropriate treatment.
Patients who have developed severe hypersensitivity reactions should not be re-
challenged.

Should an infusion reaction occur the infusion should be discontinued. The symptoms
should be managed using paracetamol, with addition of chlorphenamine and
hydrocortisone if anaphylaxis suspected. Please refer to the trusts Hypersensitivity-
Management Prevention Policy for full details.

Patient should be monitored until resolution of all observed symptoms. Patients

experiencing dyspnoea at rest may be at increased risk of a fatal infusion reaction;
these patients should not be treated with trastuzumab.

Cardiotoxicity
Management of Trastuzumab and Pertuzumab-Induced Cardiotoxicity (refer to NCRI
recommendations 2009 outlined below)
 Sharp falls in LVEF (10 points or to <50%) during cytotoxic chemotherapy may
indicate increased susceptibility to cardiac dysfunction on
trastuzumab/pertuzumab. Prophylactic ACE inhibitor therapy may be considered
for such patients.
 Assessment at the end of treatment is recommended for patients requiring
cardiovascular intervention during treatment.
 Additional testing is required in patients who have LV systolic dysfunction.

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 Patients developing signs and symptoms of heart failure should have their
trastuzumab/pertuzumab treatment interrupted, receive an ACE inhibitor and be
referred to a cardiologist.
 If the LVEF falls to ≤ 40%, (representing biologically important LV systolic
dysfunction) trastuzumab/pertuzumab should be interrupted the patient should
receive an ACE inhibitor and be referred to a cardiologist for treatment.
 After trastuzumab interruption and appropriate medical therapy, LVEF should be
re-checked after 6–8 weeks. Trastuzumab may be re-initiated if the LVEF is
restored to a level above the LLN.
 If the LVEF falls to below the LLN but > 40%, trastuzumab may be continued, but
an ACE inhibitor should be initiated.
 If the patient is already on an ACE inhibitor, they should be referred to a
cardiologist.
 LVEF assessment should be repeated after 6–8 weeks.
 If the LVEF falls by 10 points or more but remains above the LLN, trastuzumab
may be continued. Intervention with an ACE inhibitor is recommended in an
attempt to reduce the risk of further LVEF decline of symptomatic CHF.
 LVEF Monitoring should be repeated after 6–8 weeks.

NCRI recommendations for cardiac monitoring

Ref: British Journal of Cancer 2009 100:684-692

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References:

Stockley’s drug interactions. Ninth edition. Edited K. Baxter. Pharmaceutical press.

London. 2010.

SmPC for Pertuzumab (Perjeta 420mg Concentrate for solution for Infusion, Roche) –
accessed via electronic medicines compendium at https://www.medicines.org.uk/emc

SmPC for Trastuzumab (Herceptin 150mg powder for concentrate for solution for
infusion, Roche) - accessed via electronic medicines compendium at
https://www.medicines.org.uk/emc

SmPC Phesgo 1200 mg/600 mg solution for injection (Accessed 15th February 2021)
https://www.medicines.org.uk/emc/product/11989

Supplement to: Krens S D, Lassche, Jansman G F G A, et al. Dose recommendations

for anticancer drugs in patients with renal or hepatic impairment. Lancet Oncol 2019;
20: e201–08.

APHINITY Trial
NEJM 2017: 377:122-131

TRYPHAENA trial
Annals of Oncology 24: 2278–2284, 2013

NEOSPHERE trial
Lancet Oncol 2012; 13: 25–32

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