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DOCE+PERT+TRAS

Cancer Type: Breast  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Pertuzumab-Trastuzumab - Unresectable Locally Recurrent or Metastatic - Breast Cancer
New Drug Funding Program
    Docetaxel - Metastatic Breast Cancer
A - Regimen Name

DOCE+PERT+TRAS Regimen
DOCEtaxel-Pertuzumab-Trastuzumab


Disease Site
Breast

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses
  • Treatment of patients with HER2 positive (IHC3+ or FISH/SISH ≥ 2) unresectable locally recurrent or metastatic breast cancer with an ECOG status of 0 or 1, LVEF 50% or more at baseline and who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
  • Prior anti-HER2 adjuvant therapy permissible providing relapse free interval ≥ 6 months.

 

 

 


Supplementary Public Funding

PERTuzumab
New Drug Funding Program (Pertuzumab-Trastuzumab - Unresectable Locally Recurrent or Metastatic - Breast Cancer) (NDFP Website) (

Also refer to this form for trastuzumab NDFP funding criteria.

)

DOCEtaxel
New Drug Funding Program (Docetaxel - Metastatic Breast Cancer) (NDFP Website)

 
B - Drug Regimen

Cycle 1 - Pertuzumab and Trastuzumab Loading Dose 3:

PERTuzumab
840 mg IV over 60 min Day 1
trastuzumab
8 mg /kg IV over 90 min Day 1
DOCEtaxel

1

75 mg /m² IV Day 1
 
Cycle 2 and Onwards - Pertuzumab and Trastuzumab Maintenance Dose3:
PERTuzumab

1, 2, 4

420 mg IV over 30* to 60 min Day 1

(* if previous 60-minute infusion well-tolerated)

 
trastuzumab

1, 2, 4

6 mg /kg IV over 30** min Day 1

(**if previous 90-minute infusion well-tolerated)

 
DOCEtaxel

*, 1, 2

75 to 100 mg /m² IV Day 1
 
*May consider dose escalation to 100mg/m2 if the patient tolerated at least one cycle of 75 mg/m2 without the following events:  febrile neutropenia, grade 4 neutropenia for > 5 days, any ANC of < 0.1 x 10 9/L for >1 day , or other ≥grade 3 non-hematologic toxicities.
1 In the CLEOPATRA trial, pertuzumab was given on day 1, followed by trastuzumab and docetaxel on day 2 . From cycle 2 and onwards, all drugs were given on day 1 if tolerated.
2 In the PERUSE trial, pertuzumab, trastuzumab and the taxane were given in any order from cycle 2 and onward.
3 If delayed by ≥ 3 weeks (i.e. ≥ 6 weeks from last dose), consider reloading with loading dose.
4 Discontinue pertuzumab if trastuzumab is discontinued. May continue trastuzumab and pertuzumab after docetaxel discontinued, in the absence of disease progression.
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C - Cycle Frequency

REPEAT EVERY 21 DAYS

Until disease progression, no evidence of further response, or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low (docetaxel)

Other Supportive Care:

  • Dexamethasone 8 mg bid po for 3 days starting 1 day prior to docetaxel (prevent anaphylaxis / fluid retention.)
  • Trastuzumab and Pertuzumab: Nausea and vomiting are usually symptoms that are related to infusion-associated reactions. To prevent recurrence of infusion-associated reactions, acetaminophen and diphenhydramine may be given as pre-medication. Refer to Trastuzumab and Pertuzumab drug monographs for full details.
 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

 

 

Dosage with toxicity

Trastuzumab and Pertuzumab:

  • Dose reductions are not recommended. Doses are held or discontinued due to toxicity.

Hematologic Toxicities:  No dose adjustments required for trastuzumab and pertuzumab.

Toxicity

Recommendation (pertuzumab and trastuzumab)

Reversible chemotherapy-induced myelosuppression

Continue pertuzumab and trastuzumab;

monitor for complications of neutropenia (i.e. infections) and treat appropriately

Severe diarrhea

Start anti-diarrheal treatment. Hold pertuzumab if no improvement; restart pertuzumab when diarrhea is under control.


Cardiotoxicity:

Left Ventricular Ejection Fraction
Trastuzumab and Pertuzumab
 
Action
LVEF at re-assessment
Dose
<40% and asymptomatic
Hold and repeat MUGA in 3 weeks
  • >45% OR
  • 40-45% and <10% ↓ from baseline
Restart
40-50%* AND ≥10% points below baseline, and asymptomatic
  • <40% OR
  • 40-50%* and ≥ 10% points below baseline OR
  • symptomatic
Discontinue
Symptomatic
Considering discontinuing
Not applicable
Not applicable

* In the CLEOPATRA trial, trastuzumab and pertuzumab treatments were held if LVEF is 40-45% and ≥10% below baseline and asymptomatic. At LVEF reassessment, pertuzumab and trastuzumab may restart if LVEF "≥46%" or "40-45% and <10% ↓ from baseline"; otherwise, discontinue.

 

DOCEtaxel:

Dose levels:  100mg/m2, 75 mg/m2, 55 mg/m2 

 

Toxicity (worst in previous cycle)

 

Docetaxel Dose Modification*

Febrile neutropenia / Grade 4 AGC ≥ 7 days

↓ 1 dose level (or G-CSF)

Grade 3 skin/ neuro/ major organ/ non-hematologic toxicity

↓ 1 dose level

Any occurrence of cystoid macular edema

Hold and investigate; refer patient promptly an ophthalmic examination. Discontinue if confirmed

Grade 4 skin/ neuro/ major organ/ non-hematologic toxicity
OR
Recurrence of Grade 3 toxicity after prior dose reduction

Discontinue
 

* Do not retreat until AGC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and toxicity ≤ grade 2.

 

Management of Hypersensitivity or Pulmonary Toxicity:

Toxicity
Management (trastuzumab, pertuzumab or docetaxel infusions)
Mild hypersensitivity reaction

↓ infusion rate (and/ or hold)  and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate. Consider premedication for next infusion.

Moderate hypersensitivity reaction

Hold and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate; complete infusion at ↓ rate if possible. Use premedication for next infusion.

Severe hypersensitivity reaction or Pulmonary Toxicity

Hold and manage symptoms aggressively with beta-agonists, antihistamines, antipyretics, and/or corticosteroids.  Discontinue permanently and do not rechallenge



Hepatic Impairment

Hepatic impairment

AST and/or ALT

 

Alk Phosp

 

Bilirubin

DOCEtaxel

 

Pertuzumab Trastuzumab
 

Mild-moderate

> 1.5 X ULN

AND

> 2.5 x ULN

 

 

Do no treat

Not been studied No change

Severe

> 3.5 x ULN

OR

> 6 x ULN

OR

> ULN

Do not treat. Discontinue if treatment already started.

Not been studied No change

Renal Impairment

Creatinine Clearance (mL/min)

pertuzumab

 

trastuzumab

 

DOCEtaxel

 

≥30                     

No adjustment required

No adjustment required

No adjustment required

<30

Not been studied

No adjustment required

No adjustment required


Dosage in the Elderly

For pertuzumab and trastuzumab, no adjustment required; the risk of cardiac dysfunction and myelosuppression may be increased in elderly patients on trastuzumab. The reported trials did not determine differences in efficacy between patients > 65 years versus younger patients.

For docetaxel, no adjustment required, but caution should be exercised in elderly patients with poor performance status.

 

 


 
F - Adverse Effects

Refer to pertuzumab, trastuzumab, DOCEtaxel drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Alopecia
  • Diarrhea (may be severe)
  • Fatigue
  • Myelosuppression +/- infection, bleeding (may be severe)

 

  • Neuropathy (may be severe)
  • Skin reactions (may be severe)
  • Edema
  • Nausea, vomiting
  • Mucositis
  • Nail disorder (may be severe)
  • Anorexia, weight loss
  • Headache
  • Cough, dyspnea (may be severe)
  • Musculoskeletal pain
  • Hypersensitivity (may be severe)
  • Fever
  • Dysgeusia
  • Insomnia
  • Dizziness
  • Dyspepsia
  • Hypertension
  • Cardiotoxicity
  • Arrhythmia
  • Arterial thromboembolism
  • Venous thromboembolism
  • GI obstruction, perforation
  • Pancreatitis
  • Renal failure
  • Cystoid macular edema
  • Secondary malignancy
  • Seizure

 

 
G - Interactions

Refer to pertuzumab, trastuzumab, DOCEtaxel drug monograph(s) for additional details


  • Avoid concomitant use with anthracyclines or other cardiotoxic drugs (extreme caution with anthracyclines up to 27 weeks after stopping trastuzumab)
  • Avoid use of docetaxel with CYP3A4 inhibitors (consider reduced dose if must use together for strong inhibitors)
  • Avoid use of dronedarone with docetaxel given increased risk of toxicity
  • Caution and monitor with CNS depressants (ethanol in docetaxel formuations may cause intoxication)
 
H - Drug Administration and Special Precautions

Refer to pertuzumab, trastuzumab, DOCEtaxel drug monograph(s) for additional details


Administration: pertuzumab

  • Dilute required dose in 250 mL Normal Saline.  Do not administer as an intravenous push or bolus.
  • Avoid shaking the solution in order to avoid foaming.
  • Give loading dose IV over 60 minutes; maintenance dose should be given IV over 30-60 minutes.
  • Monitor patient for 60 minutes after the first infusion, and 30 minutes after subsequent doses for any infusion reactions before starting trastuzumab.
  • Do not use D5W for dilution since pertuzumab is chemically and physically unstable in this solution.  Do not admix with other drugs.
  • Compatible with PVC, polyethylene or non-PVC polyolefin bags
  • Refrigerate unopened vials at 2-8°C; protect from light.

 

Administration: trastuzumab

  • NOTE:  Herceptin® (trastuzumab) and Kadcyla® (trastuzumab emtansine) are NON-INTERCHANAGEABLE. There have been fatal reports where the incorrect trastuzumab product was administered to patients with breast cancer in the clinical trials setting.
  • Mix in 250 mL bag NS. Do not use D5W as it causes protein aggregation. Do not shake.
  • Infuse loading dose IV over 90 minutes; subsequent infusions may be given over 30 minutes if the initial loading dose is well-tolerated.
  • DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.
  • Should not be mixed or diluted with other drugs.
  • Diluent supplied - Bacteriostatic Water for Injection (BWFI) - contains benzyl alcohol 1.1%; if patient is hypersensitive to benzyl alcohol, may reconstitute with Sterile Water for Injection, but must be used immediately and discard unused portion.
  • Solution reconstituted with the supplied BWFI is stable up to 28 days refrigerated.
  • Do not freeze the reconstituted solution.

 

Administration: DOCEtaxel

  • Mix in 250mL D5W or NS to a maximum concentration of 0.3-0.74 mg/mL.  For doses over 185 mg, use a larger volume of the infusion vehicle so the maximum concentration is not exceeded.
  • ALWAYS premedicate with dexamethasone.  Infuse through main IV line over 1 hour.
  • Use non-PVC equipment to minimize patient exposure to DEHP.
  • To minimize hypersensitivity reactions, docetaxel infusion should be started at a slow rate, then increased incrementally to planned rate (e.g. infuse at an 8 hourly rate for 5 minutes, then at a 4 hourly rate for 5 minutes, then at a 2 hourly rate for 5 minutes, then finally, resume at the 1 hourly infusion rate).

Contraindications:

  • Patients with known hypersensitivity to trastuzumab, pertuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any components of these drugs
  • Trastuzumab should only be used in patients whose tumours overexpress HER2
  • Patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80
  • Patients with neutrophil counts of <1500 cells/mm3 or with severe liver impairment.

Precautions:

  • The risk of cardiotoxicity must be weighed against the potential benefits of treatment, especially in older patients, patients with pre-existing cardiac disease (including LVEF < 55%) and patients who have had prior cardiotoxic therapy. Note: in the adjuvant trials, patients with cardiac risk factors were excluded from the trials.
  • Exercise caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumour involvement, as they may experience more severe lung toxicities. 
  • Use with caution before or after anthracyclines (for up to 27 weeks after trastuzumab discontinuation due to long half-life).
  • Life-threatening infusion-related reactions associated with the administration of trastuzumab may occur. See Adverse Effects for recommended precautions, monitoring, and treatment
  • Use with caution in patients with pre-existing effusions or ascites.
  • Docetaxel contains ethanol and may be administered with agents such as antihistamines which may cause drowsiness. Patients should be cautioned regarding driving and the use of machinery immediately after receiving the infusion. Ethanol may be harmful to patients at risk of adverse effects such as those with alcoholism, liver disease, epilepsy and children. Cases of alcohol intoxication have been reported.

Pregnancy & lactation:

  • Pertuzumab and trastuzumab are contraindicated in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for 7 months after the last dose.
  • Monitor for oligohydramnios in patients who become pregnant during pertuzumab therapy. Perform appropriate fetal testing if oligohydramnios occurs. The efficacy of intravenous hydration in the management of oligohydramnios due to pertuzamab is not known.
  • Breastfeeding is not recommended

 

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • CBC, including nadir counts; baseline and before each cycle
  • Cardiac assessment, including evaluation of left ventricular function (Echocardiogram or MUGA scan); more frequent with asymptomatic reductions in LVEF; baseline, q3 months during treatment, then q6 months after trastuzumab and pertuzumab discontinuation x2 years
  • Liver function tests; baseline and before each cycle
  • Clinical toxicity assessment of infection, bleeding, neurotoxicity, fluid retention, hypersensitivity, lethargy, cutaneous reactions, thromboembolism, cardiovascular, musculoskeletal pain, ophthalmic, GI or respiratory effects; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
First cycle: 1.5 hours (day 1), 3 hours (day 2); Subsequent cycles: 2.5 - 4 hours
Pharmacy Workload (average time per visit)
38.687 minutes
Nursing Workload (average time per visit)
94.167 minutes
 
K - References

Bachelot T, Ciruelos E, Peretz-Yablonski T, et al. A single-arm phase IIIb study of pertuzumab and trastuzumab with a taxane as first-line therapy for patients with HER2-positive advanced breast cancer (PERUSE). Cancer Research 2012; 72(24 Suppl 3):OT1-1-02.

Bachelot T, Ciruelos E, Peretz-Yablonski T, et al. A single-arm phase IIIb study of pertuzumab and trastuzumab with a taxane as first-line therapy for patients with HER2-positive advanced breast cancer (PERUSE)  [Presentation].  Slides from San Antonio Breast Cancer Symposium 2012.

Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366(2):109-19.

Docetaxel, pertuzumab, trastuzumab drug monographs, Cancer Care Ontario.

Swain SM, Ewer MS, Cortés J, et al. Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study.  Oncologist 2013;18(3):257-64.

Swain SM, Kim SB, Cortés J, et al.  Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.  Lancet Oncol 2013;14(6):461-71.

October 2017 edited drug regimen, added interactions, admin & precautions


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
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