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REGO

Cancer Type: Gastrointestinal, Gastrointestinal Stromal Tumours, Sarcoma, GIST  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    regorafenib - For the treatment of metastatic and/or unresectable gastrointestinal stromal tumors (GIST), according to specific criteria.
A - Regimen Name

REGO Regimen
Regorafenib


Disease Site
Gastrointestinal - Gastrointestinal Stromal Tumours
Sarcoma - GIST

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 adult patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) who have had disease progression on or intolerance to imatinib and sunitinib treatment


Supplementary Public Funding

regorafenib
Exceptional Access Program (regorafenib - For the treatment of metastatic and/or unresectable gastrointestinal stromal tumors (GIST), according to specific criteria. ) (EAP Website)

 
B - Drug Regimen

regorafenib
160 mg PO Daily for 21 days of a 28-day cycle

(Outpatient prescription in 40mg tablets)

 

 

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C - Cycle Frequency

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

  • Prevention of palmar-plantar erythrodysesthesia (PPE) includes control of calluses and minimizing pressure stress to soles and palms. Management may include the use of keratolytic creams (e.g. urea, salicylic acid, or alpha hydroxyl acid-based creams applied sparingly only on hyperkeratotic areas) and moisturizing creams (applied liberally) for symptomatic relief. (Also refer to dose modifications section.)

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.

Dosage with toxicity

Dose levels: 160 mg, 120 mg, 80 mg.  Discontinue if 80mg is not tolerated (after dose reduction) or more than a 4-week hold is required for toxicity.

Toxicity
Grade
Management
Hand-foot syndrome/reaction (PPE)
2

For 1st occurrence continue therapy with ↓1 dose level.  If not ≤ grade 1 within 7 days, hold drug until ≤ grade 1.  If recurs, hold until ≤ grade 1 and ↓ 1 dose level

3

Hold for ≥7 days until Grade ≤1,
↓ 1 dose level

(Continued on next page)

Toxicity (Continued)

Grade
Management
Hypertension

2 or 3

Start / increase antihypertensive. If symptomatic, hold until controlled, otherwise continue regorafenib. If cannot control with antihypertensives, ↓ 1 dose level

4
Discontinue
Hepatotoxicity (AST/ALT)
2

If bilirubin < 2 x ULN - ↓ 1 dose level;

If bilirubin ≥ 2 x ULN - discontinue

3

If bilirubin < 2 x ULN, discontinue; if must continue (i.e.  benefit > risk) - hold until AST/ALT ≤ grade 1 or baseline then ↓ 1 dose level; if recurs → discontinue.

If bilirubin ≥ 2 x ULN - discontinue

4
Discontinue
Pneumonitis
Any grade

Hold and investigate.  If confirmed, discontinue

Cardiac ischemia
 
Hold; consider discontinuing

GI perforation or fistula, arterial thromboembolism, RPLS, wound dehiscence, severe dermtaologic reaction (SJS/TEN), severe hemorrhage, intolerance of 80mg dose level

Any grade

Discontinue
Other toxicity
3

Hold until ≤ grade 1 then ↓ 1 dose level

4

Discontinue; if benefit > risk and regorafenib must be restarted, reduce by 1 dose level



Hepatic Impairment

Starting Dose:
Patients with mild and moderate hepatic impairment experienced a higher incidence of adverse events then patients with normal hepatic function at baseline. Asian patients are more likely to experience hepatotoxicity.

  • No dose adjustment is required in patients with mild hepatic impairment.
  • Limited data suggest exposure in patients with moderate hepatic impairment is similar to that seen in patients with normal hepatic function. Monitor patient closely.
  • Regorafenib should be avoided in patients with severe hepatic dysfunction as it has not been studied in this population.
 

Renal Impairment

  • No dose adjustment is required in patients with mild renal impairment (CrCl 60-90 mL/min)
  • Limited data suggest exposure in patients with moderate renal impairment is similar to that seen in patients with normal renal function. Monitor patient closely.
  • Regorafenib has not been studied in patients with severe renal impairment or ESRD.

Dosage based on gender:

Female patients have higher overall incidence of adverse effects as compared to males (50% vs 40%).
 

Dosage based on ethnicity:

Several studies suggest similar exposure in various Asian populations (Chinese, Japanese, Korean) as in Caucasians. A higher incidence of PPE, severe liver function test abnormalities and hepatic dysfunction was observed in clinical trials in Asian (Japanese in particular) patients as compared with Caucasians. Severe liver injury with fatal outcome was reported in 1.5% of Japanese patients as compared with <0.1% in non-Japanese patients.

 

Children:

Regorafenib should not be used in children or adolescents as efficacy and safety in patients aged less than 18 have not been established. Abnormalities in dentition, epiphyseal hypertrophy and adverse effects in the reproductive system have been documented in juvenile animal studies. 


Dosage in the Elderly

No dose adjustments are required.  Higher incidences of grade 3 and 4 hypertension were reported in patients > 65 years of age in the GIST phase III study.

 


 
F - Adverse Effects

Refer to regorafenib 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

  • ↑ LFTs (may be severe)
  • Fatigue
  • Electrolyte abnormalities

 

  • Anorexia, weight loss
  • Palmar-plantar erythrodysesthesia
  • ↑ amylase/lipase
  • Diarrhea
  • Myelosuppression ± infection 
  • Hypertension (may be severe)
  • Dysphonia
  • Pain
  • Rash (may be severe)
  • Hemorrhage (may be severe)
  • Mucositis
  • Musculoskeletal stiffness
  • Headache
  • Cardiotoxicity
  • Arrhythmia, QT prolonged
  • Arterial thromboembolism
  • GI fistula or perforation
  • Delayed wound healing
  • Cholecystitis
  • DIC
  • RPLS/PRES
  • Renal failure
  • Squamous cell carcinoma
 
G - Interactions

Refer to regorafenib drug monograph(s) for additional details


  • Regorafenib is metabolized by CYP3A4; avoid concomitant administration with strong CYP3A4 inhibitors or inducers.
  • Regorafenib inhibits BCRP and may increase the concentration of BCRP substrates.
  • Regorafenib is a P-glycoprotein inhibitor and may increase the concentration of Pgp substrates.
  • Regorafenib and its active metabolites are inhibitors of UGT1A1 and UGT1A9; they can increase exposure to substrates of these enzymes (e.g. irinotecan).
  • Antibiotics may decrease the enterohepatic circulation of regorafenib and affect regorafenib exposure, although the clinical significance is unknown. 
 
H - Drug Administration and Special Precautions

Refer to regorafenib drug monograph(s) for additional details


Drug Administration:

  • Swallow tablets whole with a glass of water, after a low-fat (<30% fat) and low-calorie (~300-550 calories) meal.
  • Take the dose at the same time each day.
  • A missed dose should be taken as soon as remembered on the same day. Otherwise, skip this dose and take the next dose on the following day. Do not take two doses ont he same day.
  • Store tablets in their original container at 15-30ºC.
  • Do not remove desiccant from bottle and keep tightly closed. Protect from moisture.
  • Discard the tablets after the bottle has been opened for 7 weeks.

Contraindications:

  • Regorafenib is contraindicated in patients who have a hypersensitivity to this drug or any of its components, to sorafenib, or to any drugs in the same class.
  • Do not use with severe hepatic impairment.

Other Warnings/Precautions:

  • Blood pressure should be controlled before initiating regorafenib.
  • Stop regorafenib at least 2 weeks before scheduled surgery as it may suppress wound healing. 
  • Exercise caution in patients with ischemic heart disease, low baseline heart rate (<60bpm), history of syncope or arrhythmia, sick sinus syndrome, SA block, AV block, CHF or on concomitant medications that decrease heart rate.
  • Patients on warfarin should be monitored closely due to increased risk of bleeding.
  • Mild hyperbilirubinemia may occur in patients with Gilbert's syndrome.

Pregnancy and Lactation:

  • Excretion into breast milk has been documented in animals
    Breastfeeding is not recommended.
  • Embryotoxicity and teratogenicity have been documented in animals. Adequate contraception should be used by both sexes during treatment, and for at least 8 weeks after the last dose.
 
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 pressure; baseline and weekly for the first 6 weeks of therapy, then prior to every cycle or more often if required
  • Electrolytes, including phosphate, calcium, sodium, potassium; baseline and as clinically indicated
  • Lipase, amylase; as clinically indicated
  • Liver function tests (ALT, AST, bilirubin); baseline and at least every 2 weeks during the first 2 months of therapy then at least monthly and if clinically indicated
  • Thyroid function tests; baseline and as clinically indicated
  • Clinical toxicity assessment for rash, fatigue, hand-foot syndrome, cardiovascular or GI effects, bleeding, neurologic or pulmonary symptoms; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • INR; more frequently in patients receiving warfarin
  • Renal function tests; As clinically indicated

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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381(9863):295-302.

Regorafenib drug monograph, Cancer Care Ontario

June 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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