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Basal cell carcinoma locally advanced or metastatic sonidegib

Check for clinical trials in this patient group. Link to Australian Clinical Trials website

This protocol is based on limited evidence; please refer to the evidence section of this protocol for more information.

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Drug Dose Route
Sonidegib 200 mg ONCE a day PO

Note: Intermittent scheduling have been used and appear broadly equivalent in vismodegib and considered a class effect r

Continuous until disease progression or unacceptable toxicity

Drug status:

Sonidegib is PBS authority.

Sonidegib is unique in its documentation requirements for reimbursement. Further details and forms are found at the Department of Human Services 

Cost:
~ $7,450 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Sonidegib 200 mg (PO) ONCE a day at least one hour before, or at least two hours after a meal. Swallow capsules whole with a glass of water.

Note: Intermittent scheduling have been used and appear broadly equivalent r

Continuous until disease progression or unacceptable toxicity

Drug Dose Route
Sonidegib 200 mg ONCE a day PO

Note: Intermittent scheduling have been used and appear broadly equivalent in vismodegib and considered a class effect r

Continuous until disease progression or unacceptable toxicity

Drug status:

Sonidegib is PBS authority.

Sonidegib is unique in its documentation requirements for reimbursement. Further details and forms are found at the Department of Human Services 

Cost:
~ $7,450 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Sonidegib 200 mg (PO) ONCE a day at least one hour before, or at least two hours after a meal. Swallow capsules whole with a glass of water.

Note: Intermittent scheduling have been used and appear broadly equivalent r

Continuous until disease progression or unacceptable toxicity

Indications

  • Locally advanced basal cell carcinoma where surgery and radiation therapy are not appropriate
  • Metastatic basal cell carcinoma

Contraindications

  • Women who are pregnant or breastfeeding
  • Women of child-bearing potential, unless two reliable methods of contraception are used during treatment and for 24 months after the last dose
  • Men whose partners are of child-bearing potential, unless two reliable methods of contraception are used during treatment and for 6 months after the last dose
Caution with oral antineoplastic agents

Select link for information on the safe prescribing, dispensing and administration of orally administered antineoplastic agents. 

Read more about oral anticancer therapy
Emetogenicity LOW

Antiemetics are not routinely required; however should a patient experience emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary may be administered.

Read more about preventing antineoplastic induced nausea and vomiting
Musculoskeletal adverse effects

Muscle spasms, pain, cramps or weakness may be caused by this treatment. Patients should be advised to promptly report any new unexplained muscle pain, tenderness or weakness during this treatment.

Patients with predisposed neuromuscular disorders or on combination therapy with other medications may have an increase risk of muscle toxicity and should be monitored closely.
Blood tests

FBC, EUC, LFTs and CK at baseline and repeat monthly during treatment or as clinically indicated.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is NOT usually recommended for patients receiving this treatment.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

The safety of having vaccinations whilst on this treatment is unknown and is therefore not recommended.
Effects of cancer treatment on fertility

This treatment can cause severe birth defects, death to an unborn baby or potential serious adverse effects during lactation. This treatment should never be used by women who are pregnant or who could become pregnant or could become pregnant within 24 months after stopping the drug.

Fertility preservation options should be discussed with all patients commencing on this treatment.

Females of reproductive potential are advised to use two reliable methods of contraception whilst on therapy and for at least 24 months following the last dose of therapy.

Male patients should use a condom with spermicide (if available), regardless of vasectomy status, when having sexual intercourse with a woman of childbearing potential during therapy and for 6 months after therapy is discontinued.
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
Creatine phosphokinase (CK) elevation and musculoskeletal adverse effects
  • For all suspected adverse effects monitor CK levels and muscle symptoms weekly until resolution to baseline, and then CK levels monthly thereafter
  • If serum creatinine is elevated, check renal function regularly and ensure that patients are well hydrated
Grade 1  No dose modifications necessary
Grade 2 without renal impairment

Delay until resolution to baseline, and resume treatment at the same dose level.

If symptoms reoccur, withhold treatment until resolution to baseline and recommence at 200 mg daily on alternate days. If symptoms persist consider discontinuing treatment. 
Grade 3 or greater without renal impairment

Delay until resolution to baseline, and resume treatment at 200 mg daily on alternate days.

CK levels should be measured weekly for 2 months after recommencement of sonidegib and monthly thereafter.
Grade 2 or greater with renal impairment

Withhold treatment and ensure patient is well hydrated.

Monitor CK and serum creatinine weekly until resolution to baseline.

Once resolution to baseline consider either recommencing treatment at 200 mg daily on alternate days whilst monitoring CK levels weekly for 2 months and monthly thereafter; or otherwise discontinue treatment permanently.
Renal Impairment 
No dose modification necessary. Very limited data is available in patients with renal impairment, these patients should be monitored carefully for adverse effects.
Hepatic impairment
No dose modifications is necessary in patients with hepatic impairment. 

References & Disclaimer

Sonidegib
  Interaction Clinical management
CYP3A4 inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased toxicity of sonidegib possible due to reduced clearance Avoid combination or monitor for sonidegib toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort, dexamethasone etc.)  Reduced efficacy of sonidegib possible due to increased clearance

Avoid combination or monitor for decreased clinical response to sonidegib.

If a strong CYP3A inducer must be used concomitantly, consider increasing the dose of sonidegib by 200 mg increments to a maximum daily dose of 800 mg.

Upon discontinuation of the strong inducer, the dose of sonidegib used prior to initiation should be resumed.
CYP2C9, CYP2B6, and breast cancer resistance protein (BCRP) substrates (e.g. warfarin, phenytoin, methadone, sulfasalazine, or methotrexate etc.) Increased toxicity of these drugs (in vitro) possibly due to competitive inhibition of CYP2C9, CYP2B6, and breast cancer resistance protein (BCRP) by sonidegib. Monitor patients closely for adverse drug reactions, especially those with a narrow therapeutic range (e.g. warfarin and phenytoin)
Agents that may increase musculoskeletal adverse effects (e.g. HMG-CoA reductase inhibitors).  Increased risk of developing musculoskeletel adverse events due to overlapping toxicities. Monitor patients closely and consider dose adjustment if muscle symptoms develop
Proton pump inhibitors (e.g. esomeprazole)

The AUC of sonidegib was reduced by 32% when combined with esomeprazole. 

The effects of this interaction upon clinical efficacy has not been determined.

 Monitor for decreased clinical response when used in combination 
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Administration

This is a continuous oral treatment

Safe handling and waste management (reproductive risk only)

Safe administration (reproductive risk only)

General patient assessment prior to each day of treatment.

Pre treatment medication

Administer antiemetics if required

Sonidegib

  • administer orally ONCE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • to be taken on an empty stomach, one hour before or two hours after food.

Note: missed doses should only be taken if within 6 hours, if more than 6 hours wait until the next dose is due. If vomiting occurs after dose, administer the next dose at the next scheduled time.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Sonidegib capsules
  • Sonidegib capsules with written instructions on how to take them.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration

Read more about taste and smell changes

Early (onset days to weeks)
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Muscle spasms

Spasms, cramping and pain in the muscle can occur causing severe discomfort 

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia

Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Menstrual abnormalities

Irregular, spotting, increased, decreased or loss of uterine bleeding.  

A search of the literature did not find strong evidence to support the use of sonidegib in the treatment of basal cell carcinoma. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II, double blinded, multicentre, international trial (BOLT) where patients were randomised to receive 200 mg or 800 mg sonidegib daily. 230 patients were randomised, 79 in the 200 mg group and 151 in the 800 mg group. The primary outcome was objective response using modified RECIST criteria. In the 200 mg group 18 of 42 patients with locally advanced disease achieved an objective response by central review and 2 of 13 patients with metastatic disease achieved an objective response. In the 800 mg group 35 of 93 patients with locally advanced disease achieved an objective response as did 4 of 23 patients with metastatic disease. Fewer adverse events leading to dose interruptions, dose reductions or treatment discontinuation occurred in patients in the 200 mg group than in the 800 mg group.r

Source Study & year published Supports use Is the dose and regimen consistent with the protocol? Comments

Phase II trial

Lear et al 2018 r

Yes

Yes

 

Guidelines

Date published/revised

Supports Use

Is the dose and regimen consistent with the protocol?

Comments

NCCN

v.1 2018

Yes

Yes 

Doses as per BOLT trialr

CCO

- 

N/A

-

-

ESMO

- 

N/A

-

-

Efficacy

A summary of the evidence supporting the effect of this protocol is below:r 

Outcome

200 mg dose arm n=79

800 mg dose Control arm n=151

No. of patients

66 patients with LABCC

13 patients with metastatic BCC

128 patients with LABCC

23 patients with metastatic BCC

Overall survival

2 years OS 93.2% for LABCC

2 year OS 69.3% for mBCC

2 year OS 90.7% for LABCC

2 year OS 69.1% for mBCC

Median survival

Not reached for LABCC or mBCC

Not reached for LABCC 

Median OS 36.7 months in mBCC

Median Progression free survival

22.1 months by central review in LABCC

13.1 months by central review in mBCC

28.0 months by central review in LABCC

11.1 months by central review in mBCC

Response rate (complete+partial)

56.1% by central review in LABCC

7.7% in metastatic BCC

45.3% by central review in LABCC

17.4% in metastatic BCC

Disease control rate Response+Stable disease

90.9% for LABCC

92.3% for metastatic BCC

 

91.3% for mBCC

Median duration of response

26.1 months by central review in LABCC

24.0 months in metastatic BCC

23.7 months by central review in LABCC

 

Toxicity

A summary of the toxicities in the 200 mg treatment arm are included in the table below. The most clinically significant toxicities for this treatment are muscle spasms and alopecia.r 

Toxicity (all grades) r Incidence of event

Muscle spasms

54%

Alopecia

49%

Dysgeusia (altered taste)

44%

Nausea

39%

Diarrhoea

32%

Weight decreased

30%

CK increased

30% 

Fatigue

30%

Appetite decreased

23%

Myalgia

19%

Vomiting

11%
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Version 1

Date Summary of changes
15/06/2018 New protocol taken to Medical Oncology Reference Committee meeting
19/12/2018 Protocol approved and published on eviQ. Review protocol in 1 year. 
31/05/2019 Protocol reviewed electronically by Medical Oncology Reference Committee. No changes. Next review in 2 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:
Last reviewed:
Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3410

26 May 2020