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DABR

Cancer Type: Skin, Melanoma  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    daBRAfenib - As monotherapy for the first-line and second-line treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic disease, according to specific criteria
A - Regimen Name

DABR Regimen
Dabrafenib


Disease Site
Skin - Melanoma

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 patients with unresectable or metastatic melanoma with a BRAF V600 mutation (identified by a validated test). (Health Canada indication)

Funding details:

First line monotherapy in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma.  Not funded by EAP in patients who have progressed on prior BRAF inhibitor treatment.  Brain metastases (if present) should be stable.

Second line monotherapy in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma for patients who have progressed after receiving chemotherapy treatment in the first line setting.  Not funded by EAP in patients who have progressed on prior BRAF inhibitor treatment.  Brain metastases (if present) should be stable.


Supplementary Public Funding

daBRAFenib
Exceptional Access Program (daBRAfenib - As monotherapy for the first-line and second-line treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic disease, according to specific criteria) (EAP Website)

 
B - Drug Regimen

daBRAFenib
150 mg PO BID
(Outpatient prescription in 50 mg or 75 mg capsules)
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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

Prophylaxis with antipyretics may be required if prior severe febrile reactions

Also refer to CCO Antiemetic Recommendations.

 
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.

A validated test is required to identify BRAF V600 mutation status. Dabrafenib should only be used in patients with BRAF mutations.  Phase II studies reported fewer responses in BRAF V600K patients compared to BRAF V600E patients.

Dose Levels:

Dose Level Dose
0 150 mg PO BID
-1 100 mg PO BID
-2 75 mg PO BID
-3 50 mg PO BID
unable to tolerate 50 mg PO BID discontinue

Dosage with toxicity

Toxicity Type  Dose
Fever of 38.5-40°C Hold until resolution; monitor creatinine and for signs and symptoms of infection. Restart at same dose or ↓ 1 dose level.  Prophylaxis with antipyretics may be required if prior severe febrile reactions
Fever > 40°C or any fever with complications due to rigors, hypotension, dehydration or renal failure

 

Monitor creatinine and for signs and symptoms of infection.

Discontinue
OR
Hold until ≤ grade 1 and ↓ 1 dose level.  Prophylaxis with antipyretics may be required if prior severe febrile reactions.
Uveitis that responds to local ocular therapies Continue treatment without dose modifications and monitor 
Uveitis that does not improve despite local ocular therapy Hold until resolved and ↓ 1 dose level
Pancreatitis

Hold until resolved.  Discontinue OR

If restart, ↓ 1 dose level and monitor carefully.

Cutaneous squamous cell carcinoma or new primary melanoma No dose modification or interruptions recommended.
RAS associated malignancy Consider risk benefit before making decision to continue treatment
Other Grade 1 or tolerable Grade 2 No change; monitor.
Other intolerable Grade 2 or Grade 3 Hold until ≤ grade 1 and restart by ↓ 1 dose level
Other Grade 4

Discontinue on 1st occurrence OR hold until ≤ grade 1 and restart by ↓ 1 dose level

If recurs, discontinue.



Hepatic Impairment

Hepatic metabolism and biliary secretion are the main routes of dabrafenib elimination; hepatic impairment may lead to increased exposure and toxicities.  Population pharmacokinetics in mild hepatic impairment suggest no dose adjustment is required, but no data are available for moderate to severe hepatic impairment.  (Continued on next page)

Hepatic Impairment Dose
Mild No dose adjustment required.
Moderate No data
Severe No data

Renal Impairment

Threre are no clinical data in patients with severe renal impairment. With mild to moderate impairment, population pharmacokinetics suggest that no adjustments are required.

Creatinine clearance  Dose
30-89 mL/min No dose adjustment needed
 < 30 mL/min No data found. Use with caution.

 

Dosage in the elderly

More adverse events were observed in elderly patients (≥ 65 years). No dose adjustment required.

 

Children

Safety and efficacy have not been established in children and adolescents. Adverse growth effects and renal toxicity have been observed in developing animals. 


 
F - Adverse Effects

Refer to dabrafenib 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

  • Hyperglycemia
  • Abnormal electrolyte(s) (PO4, Na)
  • Hyperkeratosis
  • Headache, musculoskeletal pain
  • Febrile reactions (may be severe)
  • Alopecia
  • Nausea/vomiting
     
  • New primary or secondary malignancies (cutaneous or non-cutaneous)
  • ↑ LFTs
  • Fatigue
  • Hand-foot syndrome
  •  Rash
  • Nasopharyngitis
  • Diarrhea
  • Edema
  • Cough
  • Constipation
  • Anorexia
  • Hemorrhage
  • Myelosuppression
  • Photosensitivity
  • Arrhythmia
  • Venous thromboembolism
  • QT prolongation
  • Worsening of heart valve disease
  • Hypersensitivity
  • Pancreatitis
  • Renal failure
  • Nephritis
  • Uveitis/ retinal vein occlusion/ retinal pigment epithelial detachment
  • Cardiotoxicity 
 
G - Interactions

Refer to daBRAFenib drug monograph(s) for additional details


  • No clinically relevant interactions with drugs altering upper GI pH
  • CYP3A4 & CYP2C8 inducers ↓ dabrafenib concentration and/or efficacy. Avoid strong inducers if possible.
  • CYP3A4 & CYP2C8 inhibitors ↑ dabrafenib and metabolite exposure and/or toxicity. Avoid strong inhibitors if possible.
  • Dabrafenib is a moderate to strong CYP3A4 inducer and will ↓ CYP3A4 substrate exposure and/or efficacy. Caution; monitor for efficacy.
  • Increased risk of QT prolongation with other drugs that prolong QTc. Avoid if possible.
  • Dabrafenib can increase the metabolism of substrates of CYP2B6, 2C8, 2C9, 2C19, UGTs and Pgp; use alternate medications if possible or monitor for efficacy. 
 
H - Drug Administration and Special Precautions

Refer to daBRAFenib drug monograph(s) for additional details


Administration

  • Dabrafenib doses should be given approximately 12 hours apart on an empty stomach, at least 1 hour before or 2 hours after a meal.
  • Do not administer with high fat meals.
  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
  • If a dose is missed, it may be given if there are more than 6 hours before the next dose.  Otherwise, skip this dose and give the next one as scheduled.  Never give both doses at the same time.


Contraindications

  • Patients who have a hypersensitivity to this drug or any of its components
  • Patients with BRAF wild-type or unknown disease.  BRAF mutation must be confirmed using a validated test before starting dabrafenib treatment.


Precautions

  • Dabrafenib monotherapy has not been studied in patients who have had previous treatment with BRAF inhibitors.
  • Exercise caution in patients with risk factors for QT prolongation or Torsades de pointes (low potassium/magnesium, congenital QT prolongation, or history of arrhythmia, CHF, anti-arrhythmics, other QTc prolonging agents, prior anthracyclines), diabetes, autonomic neuropathy.
  • Patients were excluded from clinical trials if they had abnormal heart valve morphology ≥ grade 2.
  • Monitor for hemolytic anemia in patients with G6PD deficiency as dabrafenib contains a sulfonamide moiety
  • Dabrafenib is not recommended for use in pregnancy.  Highly effective contraception (<1% pregnancy rate) should be used by both sexes during treatment, and for at least 4 weeks after treatment cessation of dabrafenib.  Efficacy of hormonal contraceptives can be decreased by dabrafenib (refer to Interactions); therefore effective non-hormonal contraception methods should be used.
  • Breastfeeding is not recommended.
  • Fertility effects may be irreversible.
 
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

  • Blood glucose; baseline and periodic, more regularly in patients with diabetes or hyperglycemia
  • Blood pressure; baseline and periodic
  • Electrolytes, including phosphate; baseline and periodic
  • Liver function tests; baseline and regular
  • Renal function tests; baseline, regular, during and after severe febrile events
  • Non-cutaneous malignancies; baseline, periodic or as clinically indicated during treatment, up to 6 months after the last dose
  • Skin examination for cutaneous squamous cell carcinoma and new primary melanoma; baseline, every 2 months during treatment, then every 2 to 3 months for 6 months after the last dose.  
  • Clinical toxicity assessment for febrile events, pancreatitis, musculoskeletal pain, ocular and cardiac effects, hypersensitivity; regular
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

INR for patients receiving warfarin; baseline and periodic


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J - Administrative Information

Outpatient prescription for home administration

 


 
K - References

Dabrafenib drug monograph, Cancer Care Ontario.

Hauschild A, Grob JJ, Demidov LV, et al.  Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.  Lancet 2012 Jul 28;380(9839):358-65.

Long GV, Trefzer U, Davies MA, et al.  Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial.  Lancet Oncol 2012;13(11):1087-95.

May 2019 Updated emetic risk category


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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.
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