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CRIZ

Cancer Type: Lung, Non-Small Cell  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
  • crizotinib - ALK-positive advanced NSCLC, according to specific criteria
A - Regimen Name

 

CRIZ Regimen
Crizotinib

 

 

Disease Site
Lung - Non-Small Cell

 

 

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

Monotherapy for treatment of locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive (funded) or ROS1-positive (not currently publicly funded). 

Funding criteria include:

First-line therapy for patients with ALK-positive advanced NSCLC with ECOG performance status ≤ 2.

Second-line therapy for crizotinib-naïve patients with ALK-positive advanced NSCLC with ECOG performance status ≤ 2. Patients who have progressed during or following first-line therapy with crizotinib are not eligible to receive crizotinib as a second-line therapy.

 

 

 

Supplementary Public Funding

crizotinib
Exceptional Access Program (crizotinib - ALK-positive advanced NSCLC, according to specific criteria) (EAP Website)
 

 

 
B - Drug Regimen

 

crizotinib
 
250 mgPOBID

(outpatient prescription; available in 200 mg or 250 mg capsules)

 

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C - Cycle Frequency

 

CONTINUOUS TREATMENT

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

 

 
D - Premedication and Supportive Measures
 
Antiemetic Regimen:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

 
E - Dose Modifications

 

Use only in patients with known ALK-positive or ROS1-positive NSCLC confirmed using a validated assay. 

Avoid using concomitantly with strong CYP3A4 inducers/inhibitors, or CYP3A4 substrates with narrow therapeutic indices and associated with severe arrhythmias.  Correct electrolyte abnormalities prior to initiating treatment.

The following recommendations have been adapted from clinical trials or product monographs and could be considered.

 

Dosage with toxicity

 

Dose level
0
-1
-2
-3
Oral Dose
250mg bid
200mg bid
250 mg once daily
Discontinue

 

Worst grade toxicity
Action
Dose if resume
Grade 3 hematologic
Hold until recovery to ≤ Grade 2
100%
Grade 4 hematologic
Hold until recovery to ≤ Grade 2

↓ 1 dose level

 

Grade 3 or 4 AST/ALT

with ≤ Grade 1 bilirubin

Hold until recovery to ≤ Grade 1 or baseline

↓ 1 dose level
QTc ≥ 500 msec without arrhythmia

Hold until ≤ 470 msec and correct electrolyte abnormalities

 

↓ 1 dose level
Grade 2 or 3 bradycardia

(< 60 bpm; symptomatic, may be severe and medically significant, medical intervention indicated)

Hold immediately, evaluate contributing medications.* (see a. and b.)

 

a. If contributing concomitant medication is identified and is adjusted/discontinued

100%*

b. If there is no contributing concomitant medication or if concomitant medications are not adjusted/ discontinued

 

↓ 1 dose level*
Grade 4 bradycardia

(life-threatening consequences, urgent intervention indicated)

Hold immediately, evaluate contributing medications.* (see c. and d.)

 

c. If no contributing concomitant medication identified

Discontinue permanently

d. If contributing concomitant medication is identified and adjusted/discontinued

↓ 2 dose levels* and monitor carefully

Discontinue if recurs

Signs or symptoms of pneumonitis

Hold and investigate; discontinue permanently if confirmed.

 
Not applicable
Severe visual loss (best corrected vision < 20/200 in one or both eyes)Discontinue and evaluate severe vision lossNo data to support resuming;  risk benefit must be assessed

Bilirubin ≥ grade 2 and AST/ALT ≥ grade 2

Discontinue permanently       

Not applicable

QTc ≥ 500 msec (or > 60 msec change from baseline) and Torsade de Pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmias

Discontinue permanently
Not applicable

*Do not restart until heart rate ≥ 60 bpm and asymptomatic

 

 

Hepatic Impairment

Crizotinib has not been studied in patients with severe hepatic impairment.  Patients with bilirubin >1.5 x ULN or AST/ALT > 2.5 x ULN (>5 x ULN with metastases) were not included in clinical trials.  Exercise caution in patients with hepatic impairment.

 

Renal Impairment

No studies have been conducted in patients with severe renal impairment (< 30 mL/min) requiring dialysis. 

Creatinine Clearance (mL/min)
Starting Dose
≥60
 100% dose
>30-60
 100% dose; use with caution
<30 (not on dialysis)
 50% dose
<30 (on dialysis)
 No info available
 

Dosage in the Elderly

There were no overall differences in safety or efficacy between patients aged 65 or older and younger patients and dosage adjustment is not required. However, edema, constipation, dysgeusia and nausea were reported more frequently in older patients. 

Dosage based on ethnicity

Although exposure is higher in Asian patients, there is no increase in the incidence of grade 3 or 4 adverse events.

Children

The safety and efficacy of crizotinib have not been established in pediatric patients. Effects on growth are likely. CNS hemorrhage was reported in pediatric trials. 

 

 
F - Adverse Effects

Refer to crizotinib 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

  • Visual disorders (may be severe)
  • Diarrhea
  • Nausea, vomiting 
  • Edema
  • Constipation
  • Increased LFTs (may be severe)
  • Anorexia
  • Fatigue
  • Abdominal pain
  • Dysgeusia
  • Upper respiratory tract infections
  • Neuropathy
  • Fever
  • Cough, dyspnea
  • Dizziness
  • Musculoskeletal pain
  • Bradycardia
  • Dyspepsia
  • Dysphagia
  • Myelosuppression +/- infection or bleeding (may be severe)
  • Rash
  • QT interval prolonged
  • Arterial/venous thromboembolism
  • Hypotension, syncope
  • DIC
  • Pneumonitis
  • Renal failure

 

 

 
G - Interactions

Refer to crizotinib drug monograph(s) for additional details

 
  • Avoid use with strong CYP3A4 inhibitors and inducers.
  • Avoid CYP3A4 substrates with narrow therapeutic index and associated with severe arrhythmias
  • Avoid (where possible) drugs that disrupt electrolyte levels and those that prolong the QT interval 
  • Avoid (where possible) drugs that decrease heart rate 
 
H - Drug Administration and Special Precautions

Refer to crizotinib drug monograph(s) for additional details

 

Administration:

  • Oral self-administration; drug available by outpatient prescription.
  • Swallow capsules whole with a glass of water; may be administered with or without food.
  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during crizotinib treatment
  • If a dose is missed, patient may take within 6 hours of missed dose.  If more than 6 hours, the dose should be skipped and taken at the next planned time.
  • Store at room temperature

Contraindications:

  • Patients with congenital long QT syndrome or persistent QTcF ≥ 500 msec
  • Patients who have a hypersensitivity to this drug or any of its components
  • Patients with ALK-negative or ROS1-negative NSCLC

 

Other Warnings/Precautions:

  • Use with caution in patients who are at risk of QT prolongation or bradycardia (low potassium/magnesium, congenital QT prolongation, CHF, anti-arrhythmics, other QTc prolonging agents, prior anthracyclines, AV block, sick sinus, sinoatrial block or drugs leading to bradycardia).
  • Caution with driving or using machinery due to vision disorder including diplopia, photopsia, blurred vision, visual impairment and vitreous floaters.
  • Use with caution in patients who have bradycardia at baseline (< 60 bpm), and in patients with cardiac disease, history of arrhythmias or who are on medications that may reduce heart rate.
  • Use with caution in patients with a history of thrombotic events, patients with hepatic impairment or severe renal impairment requiring dialysis.
 
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; baseline and at each visit; more frequent with severe myelosuppression, fever and/or infection.
  • Creatinine, electrolytes, including calcium, potassium and magnesium; baseline and periodically as indicated
  • ECG, heart rate and blood pressure; baseline and periodically as indicated
  • Liver function tests; baseline, every 2 weeks during the first 2 months, then monthly and as clinically indicated (more frequent with hepatotoxicity)
  • Renal imaging and urinalysis if renal cysts develop; as indicated
  • Ophthalmoscopy with visual loss; as clinically indicated
  • Clinical toxicity assessment for signs of bleeding or infection and GI, ocular, hepatic, cardiac and nervous system effects, pneumonitis and venous thromboembolism; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • MUGA, especially for patients with cardiac risk factors; baseline and as clinically indicated

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J - Administrative Information

Outpatient prescription for home administration; available in 200 mg and 250 mg capsules.

 
 
 
K - References

Crizotinib drug monograph, Cancer Care Ontario.

Shaw AT, Kim DW, Nakagawa K, et al.  Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.  N Engl J Med 2013;368(25):2385-94. 

Shaw, AT, Ou S, Bang Y, et al. Crizotinib in ROS1-rearrangd non-small cell lung cancer. N Eng J Med 2014; 371(21): 1963-71.

Solomon BJ, Mok T, Kim DW; PROFILE1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77.

 

October 2017 added indication for ROS1-positive NSCLC; updated adverse effects and monitoring sections

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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.