DOST(MNT); CRBPPACL+DOST

Administer dostarlimab prior to the chemotherapy when given on the same day.

Every 3 weeks for 6 cycles, unless disease progression or unacceptable toxicity.

After completion of CRBPPACL+DOST, continue with dostarlimab maintenance  DOST(MNT) every 6 weeks for up to 3 years, unless disease progression or unacceptable toxicity.

Antiemetic Regimen:  Moderate + NK1 antagonist (Carboplatin AUC ≥ 5)

                                      Minimal (dostarlimab maintenance)

• Also refer to CCO Antiemetic Summary
   

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Pre-medications (prophylaxis for infusion reaction):

Dostarlimab: 

• Routine pre-medication is not recommended.
   
• May consider antipyretic and H1-receptor antagonist in patients who experienced a grade 2 infusion reaction.

Note: Pre-medication for chemotherapy was administered after dostarlimab in the RUBY trial.

Paclitaxel*:

• Dexamethasone 20 mg PO 12-and 6-hours OR Dexamethasone 20 mg IV 30 minutes pre-infusion^†
• Diphenhydramine 25-50 mg IV/PO 30-60 minutes pre-infusion
• Ranitidine 50 mg IV OR Famotidine 20 mg IV 30-60 minutes pre-infusion

^{* Consider discontinuing pre-medications for paclitaxel if there was no IR in the first 2 doses.}

_{^† Oral and IV dexamethasone are both effective at reducing overall IR rates. Some evidence suggests that oral dexamethasone may be more effective for reducing severe reactions; however, adverse effects and compliance remain a concern.}

Carboplatin:

• There is insufficient evidence that routine prophylaxis with pre-medications reduce infusion reaction (IR) rates.

• Corticosteroids and H1-receptor antagonists ± H2-receptor antagonists may reduce IR rates for some patients (e.g. gynecological patients with a platinum-free interval (PFI) >12 months or a history of drug allergy who are receiving carboplatin starting from the 7th cycle) but no optimal pre-medication regimen has been established.

Doses should be modified according to the protocol by which the patient is being treated. 

Patients should have MSI-H or dMMR tumour status confirmed by a validated test prior to starting treatment.

Avoid the use of corticosteroids or immunosuppressants before starting treatment.

Dose reductions are not recommended for dostarlimab. Doses may be delayed or discontinued based on toxicity. Refer to dostarlimab drug monograph(s) for additional details on immune-related adverse effects (irAEs).

Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions of Immune-related toxicities and their management.

Suggested Dose Levels for Paclitaxel:

Dose modifications for Carboplatin & Paclitaxel:

¹Do not start new cycle until ANC ≥ 1.5 x 10⁹/L, platelets ≥ 100 x 10⁹/L, and non-hematological toxicities have recovered to ≤ grade 2.

Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Carboplatin & Paclitaxel:

^#There is evidence that re-challenging with cisplatin after carboplatin reaction can be a viable option; however, exact cross reactivity between platinum agents is not known, but can be as high as 25%.

*Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2-receptor antagonist).

Dostarlimab:

Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions for immune-related hepatic toxicity management.  

For paclitaxel, caution and dose reduction are advised in patients with moderate to severe hepatic impairment. Patients receiving paclitaxel with hepatic impairment may be at risk of toxicity, especially severe myelosuppression.

Suggested dose modifications are: 

 Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions for immune-related renal toxicity management

 *Refer to "Other Notes" section.

No adjustment required but elderly patients are more at risk for severe toxicity. Caution should be exercised and dose reduction considered for carboplatin as elderly patients may have reduced renal function, more severe myelosuppression and neuropathy. There is limited data with dostarlimab in patients ≥ 75 years of age.

Refer to dostarlimab, PACLitaxel, CARBOplatin drug monograph(s) for additional details of adverse effects.

Refer to dostarlimab, PACLitaxel, CARBOplatin drug monograph(s) for additional details.

• Monitor INR in patients receiving warfarin and carboplatin concomitantly; warfarin dosage adjustment may be required.

• Monitor closely with nephrotoxic and ototoxic drugs (ie. aminoglycosides) given concomitantly with carboplatin due to additive effects.

• Monitor closely with phenytoin; phenytoin dose adjustment may be required while receiving paclitaxel and carboplatin.

• Avoid if possible, or caution with radiation while receiving paclitaxel; may increase the risk of radiation pneumonitis. 

Refer to dostarlimab, PACLitaxel, CARBOplatin drug monograph(s) for additional details.

Administration

PACLitaxel: 

• In order to minimize patients’ exposure to DEHP leaching from PVC bags or sets, use polyolefin or polypropylene infusion bags and polyethylene-lined administration sets (with an in-line filter no greater than 0.22 microns).
• Dilute in 500-1000 mL Normal Saline or 5% Dextrose, in a final concentration of 0.3-1.2 mg/mL and infuse over 3 hours.
• Extended infusion of paclitaxel is not recommended as primary prophylaxis to reduce paclitaxel IRs.
• Excessive shaking, agitation, or vibration may induce precipitation and should be avoided
• Precipitation may rarely occur with infusions longer than 3 hours.
   

CARBOplatin:

• Mix in 100mL to 250mL bag (5% Dextrose or Normal Saline); infuse IV over 15 to 60 minutes.
• There is insufficient evidence that routine prophylaxis with extended infusion reduces IR rates. 
• Incompatible with sets, needles or syringes containing aluminum – leads to precipitation and loss of potency.
• Protect from light.
   

Dostarlimab:

• Dilute in a 0.9% sodium chloride or D5W IV infusion bag.
• Final drug concentration after dilution should be between 2 mg/mL and 10 mg/mL.
• Gently invert infusion bag to mix. Do not shake.
• Infuse IV over 30 minutes, using a 0.2 or 0.22 micron in-line filter.
• Administer dostarlimab prior to the chemotherapy when given on the same day.
• Do not administer as IV push or bolus.
• Do not co-administer with other drugs through the same line.
• Compatible with polyvinyl chloride (PVC), platinum cured silicon or polypropylene (PP) infusion sets, fittings made from PVC or polycarbonate, and polyethersulfone (PES) in-line filters.
• Store unopened vials refrigerated (2°C to 8°C) and protect from light. Do not freeze.
   

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Contraindications

• Patients with a history of severe hypersensitivity reactions to platinum-containing compounds, dostarlimab, paclitaxel or other drugs formulated in Cremophor EL (polyethoxylated castor oil)
• Patients with pre-existing severe renal impairment
• Patients with severe myelosuppression or bleeding tumours
   

Warnings / Precautions

• Patients who have received extensive prior treatment, have poor performance status and those over 65 years of age

• Patients with abnormal renal function or who are receiving concomitant nephrotoxic drugs

• Patients who have previously experienced severe or life-threatening skin reactions on prior treatment with immune-stimulatory anticancer agents. 
   
• Dostarlimab may cause serious immune-mediated reactions affecting multiple organ systems, including GI, hepatic, renal, respiratory, endocrine and others. Use with caution and monitor closely in patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders, such as hypo or hyperthyroidism or diabetes mellitus.
   
• Paclitaxel contains ethanol, and is administered with agents such as antihistamines which cause drowsiness. Patients should be cautioned regarding driving and the use of machinery.

• Patients with conditions such as serious active infection (HIV, hep B or C), active autoimmune disease, conditions that require systemic immunosuppressive therapy and a history of interstitial lung disease were excluded from dostarlimab clinical studies.

• Avoid live vaccines. Reduced immunogenicity may occur with the use of inactivated vaccines.

Pregnancy / Lactation

• This regimen is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.
   
• Breastfeeding is not recommended during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).
   
• Fertility Effects:

  • Carboplatin: Unknown

  • Paclitaxel: Probable

  • Dostarlimab: Unknown

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Suggested Clinical Monitoring

Carboplatin drug monograph, Ontario Health (Cancer Care Ontario).

Dostarlimab drug monograph, Ontario Health (Cancer Care Ontario).

Jemperli dostarlimab for injection Product Monograph. GlaxoSmithKline Inc. Mississauga, Ontario; July 2024.

Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med. 2023 Jun 8;388(23):2145-58.

Paclitaxel drug monograph, Ontario Health (Cancer Care Ontario).

Protocol for: Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med. 2023 Jun 8;388(23):2145-58.