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A - Regimen Name

TRBC Regimen
Trabectedin


Disease Site
Gynecologic - Uterine Sarcoma
Sarcoma - Uterine

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

For the treatment of patients with metastatic leiomyosarcoma after failure of prior anthracycline and ifosfamide chemotherapy.

 
B - Drug Regimen

trabectedin
1.5 mg /m² IV over 24 hours Day 1
(This drug is not currently publicly funded for this regimen and intent)
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C - Cycle Frequency

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

Premedication with corticosteroids (i.e. dexamethasone 20mg) IV 30 minutes before each trabectedin dose is required, for hepatoprotective and anti-emetic effects.

Consider supportive care/colony stimulating factors for myelosuppression per institutional guidelines.

 
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

List A

The following criteria must be met before EACH trabectedin treatment.

  • ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin ≥ 90 g/L
  • Bilirubin ≤ ULN, AST and ALT ≤ 2.5 x ULN
  • Albumin ≥ 25 g/L
  • Creatinine clearance ≥ 30 mL/min (monotherapy)
  • ALP (of non-osseous origin) ≤ 2.5 x ULN (consider hepatic isoenzymes 5' nucleotidase or GGT, to distinguish elevations that can be osseous in origin)
  • CPK ≤ 2.5 x ULN

 

Table A - Dose Levels:  Reduced doses are not re-escalated. Discontinue if toxicity recurs after 2 dose reductions.

 

Dose

Trabectedin

Starting dose

1.5 mg/m2

First reduction

1.2 mg/m2

Second reduction

1 mg/m2

 

 

 

 

 

 

 

Table B - Dose Modifications for Toxicity:

Counts / Toxicity (worst in previous cycles)

Trabectedin Dose**

Grade 4 ANC≥ 5 days or
Febrile neutropenia or
Platelets < 25 x 109/L

↓ 1 dose level

Alkaline phosphatase > 2.5 x ULN (non-osseous)

↓ 1 dose level

AST/ALT > 2.5 x ULN and not recovered by Day 21
or
bilirubin > ULN***

↓ 1 dose level

≥ grade 3 non-hematological/organ toxicity

↓ 1 dose level

Any grade rhabdomyolysis or CPK > 2.5 ULN

Hold until recovery, consider discontinuing

Severe hypersensitivity Discontinue
Capillary leak syndrome Hold if suspected; discontinue if confirmed and treat according to institutional practice

**Do not treat until laboratory values meet conditions listed in List A and organ/non-hematologic toxicities have recovered to grade 2. Delay for a maximum of 3 weeks – if not recovered, discontinue.

***Hold trabectedin until normalizes and restart at reduced dose. If not recovered by day 21, discontinue.



Hepatic Impairment

At baseline:*

 

Parameter

≥ ULN - < 2.5 x ULN

≥ 2.5 ULN

Bilirubin

Do not treat

Do not treat

AST/ALT

No change

Do not treat

Alkaline Phosphatase

No Change

Do not treat

*Refer to Table B for dose modifications during treatment.

Renal Impairment

CrCl (ml/min)

Trabectedin

30-60

No change

< 30

Discontinue


Dosage in the Elderly

No dose adjustment needed.  No differences in safety or effectiveness were seen in patients > 65 years of age versus younger patients. 


 
F - Adverse Effects

Refer to trabectedin 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

  • Nausea and vomiting
  • Fatigue
  • Increased LFTs (may be severe)
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Increased CPK

 

  • Anorexia
  • Constipation
  • Diarrhea
  • Headache
  • Musculoskeletal pain
  • Phlebitis
  • Venous thromboembolism
  • Cardiotoxicity
  • Hypersensitivity
  • Capillary leak syndrome
  • Hypotension
  • Rhabdomyolysis
  • Renal failure

 

 
G - Interactions

Refer to trabectedin drug monograph(s) for additional details


  • Trabectedin does not appear to induce or inhibit major CYP450 enzymes, but is metabolized by CYP3A4 and susceptible to inducers or inhibitors.
  • Avoid strong CYP3A4 inhibitors if possible, or consider a trabectedin dosage reduction.
  • Avoid strong CYP3A4 inducers if possible, or monitor closely for reduced efficacy.
  • Avoid high dose phenytoin; monitor for trabectedin toxicity and risk of seizures if used together.
  • Avoid alcohol intake while on trabectedin treatment to prevent hepatotoxicity.
  • Avoid hepatotoxic drugs and use with caution along with drugs that may cause muscle damage.
 
H - Drug Administration and Special Precautions

Refer to trabectedin drug monograph(s) for additional details


Administration:

  • Avoid grapefruit, starfruit, Seville oranges, their juices or products (as well as other inhibitors of CYP3A4) during treatment (see Interactions section)
  • MUST be administered via central intravenous line.
  • Patients must receive corticosteroid premedication 30 minutes before each trabectedin dose (i.e. dexamethasone 20mg IV), as an antiemetic and to protect the liver.
  • Reconstitute with sterile water for injection as directed.
  • Further dilute in 500mL Normal Saline or D5W.
  • Compatible with PVC, glass, polyethylene (PE) containers and tubing.
  • Do not mix or dilute with other drugs or solutions.
  • Refrigerate unopened vials at 2-8°C.

Contraindications:

  • patients who have a hypersensitivity to trabectedin or any of its components
  • patients who have active, serious or uncontrolled infections
  • patients who have left ventricular injection fraction below the lower limit of normal
  • patients with active hepatitis, elevated bilirubin, or who have CPK > 2.5 times the upper limit of normal.

Warnings/precautions:

  • Exercise caution in patients with a history of ischemic heart disease or tachyarrhythmia, as trabectedin has been associated with transient heart rate increases
  • Avoid live vaccines
  • Avoid alcohol, concomitant use of other hepatotoxic drugs or drugs known to cause rhabdomyolysis.

Pregnancy and Lactation:

  • Trabectedin is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose for females (5 months for males)
  • Breastfeeding is not recommended during treatment and for 3 months after the last dose.
  • Fertility effects: Probable
 
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, prior to each cycle, and weekly for first 2 cycles, then once between cycles
  • Liver function tests and CPK; baseline and prior to each cycle, and weekly for the first 2 cycles, then once between cycles
  • Renal function tests; baseline and regular
  • LVEF; baseline and periodic (especially in patients at risk of cardiac dysfunction)
  • Albumin; if capillary leak syndrome suspected
  • Assess for cardiac, musculoskeletal, GI, hepatic and local toxicity, as well as VTE, infection and bleeding; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Pharmacy Workload (average time per visit)
27.855 minutes
Nursing Workload (average time per visit)
76.667 minutes
 
K - References

Monk BJ, Blessing JA, Street DG, et al. A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: a gynecologic oncology group study. Gynecol Oncol. 2012 Jan;124(1):48-52.

Sanfilippo R, Grosso F, Jones RL, et al. Trabectedin in advanced uterine leiomyosarcomas: a retrospective case series analysis from two reference centers. Gynecol Oncol. 2011 Dec;123(3):553-6.

Trabectedin drug monograph, Cancer Care Ontario.


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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.