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PACL(W)+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
    Paclitaxel - Metastatic Breast Cancer
A - Regimen Name

PACL(W)+PERT+TRAS Regimen
PACLitaxel (weekly)-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.

 


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.

)

PACLitaxel
New Drug Funding Program (Paclitaxel - Metastatic Breast Cancer) (NDFP Website)

 
B - Drug Regimen

Cycle 1 - Trastuzumab and Pertuzumab Loading Dose:

PERTuzumab
840 mg IV over 60 minutes Day 1
trastuzumab
8 mg /kg IV over 90 minutes Day 1
 
then,
PACLitaxel

1


(Round to nearest 1 mg)
80 mg /m² IV over 1 hour Days 1, 8
 
Cycle 2 and Onwards - Trastuzumab and Pertuzumab Maintenance Dose (Q3W) 3:
PERTuzumab
1, 2, 4
420 mg IV over 30* to 60 minutes Day 1

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

then:

trastuzumab

1, 2, 4

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

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

then,

PACLitaxel

1, 2


(Round to nearest 1 mg)
80 mg /m² IV over 1 hour Days 1, 8

(1) In the CLEOPATRA trial, pertuzumab was given on day 1, followed by trastuzumab and the taxane [docetaxel] on day 2 .  From cycle 2 and onwards, pertuzumab, trastuzumab and the taxane were given on day 1, if all 3 medications were tolerated in cycle 1
(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, reload with loading doses.  (Continued on next page)
(4) Discontinue pertuzumab if trastuzumab is discontinued. May continue trastuzumab and pertuzumab after paclitaxel discontinued, in the absence of disease progression.

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low (paclitaxel)

Other Supportive Care:

  • 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.
  • Paclitaxel: Patients should be pretreated with a corticosteroid as well as an antihistamine and a H2 blocker: For example:
  • DEXAMETHASONE 20mg PO 12 & 6 hours or 20mg IV 30 minutes before paclitaxel
  • DIPHENHYDRAMINE 50mg IV 30 minutes before paclitaxel
  • RANITIDINE 50mg IV 30 minutes before paclitaxel
 
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.

 

(Continued on next page)

 

Paclitaxel:

Dose levels: 80 mg/m², 70 mg/m², 60 mg/m². Dose re-escalations are not allowed. Discontinue treatment if toxicity recurs after 2 dose reductions.

Toxicity (Grade or Counts x 109/L)
 
Paclitaxel dose
ANC < 1.5 and/or Platelets < 100
Delay1
ANC ≤ 0.8 and/or Platelets ≤ 50
 
Delay1; ↓ 1 level for next dose
 
Grade 2 neurotoxicity
 
↓ 1 level
Other Grade 2-3 non-hematological or grade 3 neurotoxicity 2
Delay1; ↓ 1 level
Grade 4 non-hematological;            more than 2 weeks delay or             more than 2 dose reductions
Discontinue
 
1 Delay for up to 2 weeks. Start day 1 of cycle when non-hematologic toxicities recover to ≤ grade 1, platelets ≥ 100 x  109 /L, and ANC ≥ 1.5 x 109  /L; reduce dose as per table.
2 Except alopecia, fatigue, nausea. Appropriate symptom management should be provided for vomiting, diarrhea, constipation; dose modifications may not be necessary.
 

Management of Hypersensitivity or Pulmonary Toxicity :

Toxicity
Trastuzumab
Pertuzumab
Paclitaxel
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.  For paclitaxel, may resume infusion at a rate of 10% of original rate for 15 minutes, then at 25% of original rate for 15 minutes, and if no further symptoms develop, continue at original rate until infusion is complete.

Severe hypersensitivity reaction or Pulmonary Toxicity

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



Hepatic Impairment

Patients with hepatic impairment may be at risk of toxicity, especially severe myelosuppression. 

Bilirubin
AST/ALT
Paclitaxel dose (% previous dose)
Pertuzumab Trastuzumab
2-4 x ULN
 
75%
Has not been studied No adjustment required
>4 x ULN
Grade 3
25% or OMIT
Has not been studied No adjustment required

Renal Impairment

Creatinine Clearance (mL/min)

pertuzumab

(% previous dose)

trastuzumab

(% previous dose)

Paclitaxel

(% previous dose)

≥30                     

No adjustment required

No adjustment required

No adjustment required

<30

Not been studied

No adjustment required

No adjustment required


 
F - Adverse Effects

Refer to pertuzumab, trastuzumab, PACLitaxel 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)
  • Neuropathy (may be severe)
  • Musculoskeletal pain
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Nausea, vomiting
  • Hypersensitivity (may be severe)
  • Rash (may be severe)
  • Anorexia, weight loss
  • Mucositis
  • Headache
  • Cough, dyspnea (may be severe)
  • Increased LFTs (may be severe)
  • Edema
  • Fever
  • Dysgeusia
  • Fatigue
  • Insomnia
  • Dizziness
  • Dyspepsia
  • Hypertension
  • Hypotension
  • Cardiotoxicity
  • Arrhthymia
  • Arterial thromboembolism
  • Venous thromboembolism
  • GI obstruction, perforation
  • Pancreatitis
  • Secondary malignancy
  • Renal failure
  • Cystoid macular edema
  • Typhitis
  • Seizure
 
G - Interactions
Refer to pertuzumab, trastuzumab, PACLitaxel drug monograph(s) for additional details
 
H - Drug Administration and Special Precautions
Refer to pertuzumab, trastuzumab, PACLitaxel drug monograph(s) for additional details
 
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
  • Blood pressure and pulse rate monitoring during infusion, cardiac monitoring with prior arrhythmia
  • Liver and renal function tests; baseline and before each cycle
  • Clinical toxicity assessment of infection, bleeding, neurotoxicity, fluid retention, hypersensitivity, lethargy, cutaneous reactions, thromboembolism, cardiovascular, musculoskeletal pain, 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
2.5 to 3 hour (day 1; cycle 2 and onwards); 2 hours (paclitaxel-only days)
Pharmacy Workload (average time per visit)
23.58 minutes
Nursing Workload (average time per visit)
53.167 minutes
 
K - References

Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 2015 Feb 10;33(5):442-7.

Paclitaxel, pertuzumab and trastuzumab drug monographs, Cancer Care Ontario.

October 2017 edited disease site


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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.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, 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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.