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SUNI

Cancer Type: Gastrointestinal, Gastrointestinal Stromal Tumours, Sarcoma, GIST  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    SUNItinib - Unresectable or metastatic/recurrent Gastrointestinal Stromal Tumour, with specific criteria
A - Regimen Name

SUNI Regimen
SUNItinib


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 unresectable or metastatic/ recurrent gastrointestinal stromal tumour (GIST) in patients who failed imatinib mesylate (either because of disease progression or intolerance).

 


Supplementary Public Funding

SUNItinib
Exceptional Access Program (SUNItinib - Unresectable or metastatic/recurrent Gastrointestinal Stromal Tumour, with specific criteria) (EAP Website)

 
B - Drug Regimen

SUNItinib
37.5 to 50* mg PO Days 1 to 28

(Outpatient prescription in multiples of 12.5mg, 25mg and 50mg capsules)

*Consider a lower starting dose in elderly/frail patients. See section E for dose modifications for toxicity and organ dysfunction.

 

Alternative schedule:

 

SUNItinib
37.5** mg PO Daily continuous

**George et al. 2009

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C - Cycle Frequency

Standard schedule: REPEAT EVERY 6 WEEKS (4 WEEKS ON, 2 WEEKS OFF)

Alternative schedule: CONTINUOUS

Continue treatment until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

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.

Sunitinib may be given with or without food.  Daily doses should not exceed 50mg nor be decreased below 25mg. Doses should be held prior to surgery

Suggested dose levels are 50 mg, 37.5 mg and 25 mg. Doses reduced for toxicity should not be re-escalated.

Dosage with toxicity

Toxicity

Action

Dose

 

Severe hypertension

Hold and treat appropriately. 

May resume only if hypertension is controlled. 

(See Appendix 8: Management of Angiogenesis Inhibitor (AI) Induced Hypertension)

CHF, arrhythmia, ↑ QTc, AV block, pancreatitis, hepatic failure, nephrotic syndrome, RPLS,  perforation, fistula, TMA, ITP, TTP, HUS, DIC, hemolysis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme*, necrotizing fasciitis

 

Discontinue

Not applicable

Asymptomatic falls in LVEF < LLN or ≥ 20% ↓ from baseline, thrombotic microangiopathy, grade 3 hemorrhage

 

Hold until ≤ Grade 1

↓ 1 dose level

Other grade 3 non-hematological toxicity, including ↑ LFTs

 

Hold until ≤ Grade 2

↓ 1 dose level

Grade 3 or 4 hematological (excluding lymphopenia)

 

Hold until ≤ Grade 2

↓ 1 dose level

Grade 4 non-hematological toxicity, including ↑ LFTs

Discontinue

Not applicable

* may consider rechallenge at a lower dose after resolution of erythema multiforme if clinically indicated.



Hepatic Impairment

Multiple dosing pharmacokinetic studies have not been conducted; single dose studies have only been conducted in patients with mild-moderate hepatic impairment, Hepatic metabolism / excretion is significant; consider dose modification for patients with mild to moderate impairment (Child Pugh A and B).


Renal Impairment

Only single dose studies have been conducted in patients with renal impairment. No adjustment to starting dose is required in patients with mild to severe renal impairment or with end-stage renal disease. Patients with end stage renal disease on dialysis may have lower exposure than expected.  Exercise extreme caution in patients especially with severe renal impairment or ESRD, since fatal renal failure has been reported with sunitinib. Subsequent dosing should be based on tolerability.


Dosage in the Elderly

Dose modification not required; consider dose reduction for frail patients.

 


 
F - Adverse Effects

Refer to SUNItinib drug monograph(s) for additional details of adverse effects


Most Common Side Effects

Less Common Side Effects, but may be Severe or Life-Threatening

  • Myelosuppression ± infection, bleeding (may be severe)
  • Creatinine increased (may be severe)
  • Diarrhea
  • Fatigue
  • ↑ LFTs (may be severe)
  • ↑ Lipase, amylase (may be severe)
  • Nausea, vomiting
  • ↑CPK (May be severe)
  • Dysgeusia
  • Abnormal Electrolyte(s)
  • Dyspepsia
  • Mucositis
  • Anorexia, weight loss
  • Skin/hair discolouration or hypopigmentation
  • Rash (may be severe), dry skin
  • Abdominal pain
  • Hand-foot syndrome
  • Hypertension (may be severe)
  • Cardiotoxicity (may be severe)
  • Hyper-/hypoglycemia
  • Respiratory disorders
  • Constipation
  • Headache, musculoskeletal pain
  • Hypothyroidism
  • Dizziness
  • Insomnia
  • Psychiatric disorders
  • Eye disorders
  • Arterial thromboembolism
  • Venous thromboembolism
  • Adrenal insufficiency
  • Disseminated intravascular coagulation
  • Gastrointestinal fistula/perforation
  • TMA, TTP, HUS
  • Hypersensitivity
  • Idiopathic thrombocytopenic purpura
  • Arrhythmia, QT/PR interval prolonged
  • PRES, seizures
  • Tumor lysis syndrome
  • Osteonecrosis of the jaw
  • Delayed wound healing/dehiscence
  • Necrotizing fasciitis
  • Proteinuria
 
G - Interactions

Refer to SUNItinib drug monograph(s) for additional details


  • Consider sunitinib dosage reduction with strong inhibitors of CYP3A4 (e.g. azole antifungals, macrolide antibiotics, Grapefruit juice)
  • Consider sunitinib dosage adjustment with strong inducers of CYP3A4 (e.g. phenytoin, rifampin, St. John’s wort)
  • Avoid use with drugs that prolong the QT interval (e.g. amiodarone, methadone, domperidone)
  • Avoid combining with bevacizumab given increased risk of microangiopathic hemolytic anemia, hypertension and ONJ
  • Use with caution with drugs that cause hypoglycemia (e.g. sulfonylureas)
 
H - Drug Administration and Special Precautions

Refer to SUNItinib drug monograph(s) for additional details


Administration

  • Prescribed dose should be administered orally, once daily with or without food.
  • Avoid any grapefruit, starfruit, Seville oranges or their juices/products while on this treatment. (See interactions)
  • Store at room temperature (15-30°C).
     

Contraindications

  • patients who have a hypersensitivity to this drug or any of its components
  • patients with uncontrolled hypertension, abnormal ↑QT or AV block
     

Other Warnings/Precautions

  • Extreme caution should be exercised in patients at increased risk of torsade de pointes, with bradycardia, QTc prolongation, cardiac or thromboembolic risk factors, electrolyte disturbances, and in patients taking medications which prolong QTc or the PR interval.
  • Patients who had, within 12 months, cardiovascular events such as MI (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, CVA, TIA or pulmonary embolism were excluded from clinical trials. The risk versus benefit of sunitinib use should be carefully considered in these patients
  • Concomitant use of warfarin or antiplatelet agents should be avoided.
  • Hypoglycemia has been reported in both diabetic and non-diabetic patients while on sunitinib and may be severe.
  • Patients with intra-abdominal malignancies are at an increased risk of perforation.
  • Subclinical adrenal insufficiency may occur and stressed patients (surgery, trauma, etc.) should be monitored carefully.
  • Hold treatment in patients undergoing major surgical procedures. The timing of restarting sunitinib should be based on clinical judgment of recovery.
 
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; closer monitoring in diabetic patients may be needed
  • CBC; baseline and before each cycle (or at each visit for continuous schedule)
  • Dental evaluation before starting treatment with preventative dentistry as needed;
  • ECG; baseline and periodic during therapy
  • Liver function tests, with lipase and amylase; baseline and at each visit
  • LVEF in patients with cardiac risk factors; baseline and as clinically indicated
  • Renal function tests and electrolytes (including Mg, Ca, PO4); baseline and at each visit
  • Thyroid function tests; baseline then q3 months, and as clinically indicated
  • Urinalysis; baseline and periodic
  • Blood pressure and assessment for signs and symptoms of pancreatitis, hypo-/hyperthyroidism, hypertension, myopathy, delayed wound healing, TLS, thromboembolism, bleeding, cardiac effects, neurologic, GI effects, renal, adrenal insufficiency (especially with stress); at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Adrenal function tests in patients who experience stress (surgery, trauma, severe infection)

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J - Administrative Information

Outpatient prescription for home administration.


 
K - References

Demetri GD, Garrett CR, Schöffski P, et al. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012 Jun 1;18(11):3170-9.

Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomized controlled trial. Lancet. 2006;368:1329-38.

George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009 Jul;45(11):1959-68.

Sunitinib 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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