GLOF; GLOF(RAMP)

Inpatient admission may be required for cytokine release syndrome (CRS) monitoring.

Note: ST-QBP funding for ambulatory administration only

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity, up to a maximum of 12 cycles.

Use regimen code GLOF(RAMP) for cycles 1 and 2, then GLOF for subsequent cycles.

Refer to the NDFP form for details on glofitamab retreatment.

• 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 for Obinutuzumab (prophylaxis for infusion-related reactions):

Give at least 30 min to 1 hr prior to each obinutuzumab infusion:

• IV corticosteroid* (e.g. dexamethasone 20 mg or equivalent)
• Antihistamine (e.g. 50 mg diphenhydramine PO/IV)
• Analgesic/antipyretic (e.g. acetaminophen 1000 mg PO/IV)

*Corticosteroid to be completed at least 1 hr prior to infusion. Hydrocortisone should not be used as it has not been effective in reducing IR rates.

Pre-medications for Glofitamab (prophylaxis for CRS):

Cycles 1 to 3:

Give at least 30 min to 1 hr prior to each glofitamab infusion*:

• IV glucocorticoid* (e.g. dexamethasone 20 mg or equivalent)
• Antihistamine (e.g. diphenhydramine 50 mg PO/IV)
• Antipyretic (e.g. acetaminophen 1000 mg PO)

Cycle 4 and beyond:

Give at least 30 min prior to each glofitamab infusion*:

• Antihistamine (e.g. diphenhydramine 50 mg PO/IV)
• Antipyretic (e.g. acetaminophen 1000 mg PO)
• Add IV glucocorticoid* for patients who experienced CRS with previous doses

*Glucocorticoid to be completed at least 1 hour before glofitamab infusion.

Other Supportive Care:

• Consider prophylaxis against Pneumocystis jirovecii pneumonia (PJP) and herpes virus infections.
• Consider other antimicrobial prophylaxis as per local guidelines.
• Obinutuzumab and glofitamab should be administered to adequately hydrated patients.
• Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.
• Consider withholding antihypertensives (if applicable) 12 hours prior to obinutuzumab infusion, during infusion and for the first hour after administration.
• Consider withholding concomitant medications that increase bleeding risk with obinutuzumab.

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

Do not start treatment with obinutuzumab or glofitamab in patients with active infection.

Must have tocilizumab available prior to starting glofitamab (Cycles 1 and 2). 

Dose reductions are not recommended for glofitamab or obinutuzumab pre-treatment. Refer to oBINutuzumab drug monograph for additional details

Table 1 - CRS Toxicity Management

Recommendations below are based on the product monograph. Refer to Crombie et al. for alternative CRS management guidelines.

^a Grade based on American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading (Lee et al 2019).
^b Anticytokine therapy is recommended if ICANS occurs concurrently with CRS. Refer to local institutional guidelines for management of concurrent CRS and ICANS.
^c Do not give next dose unless symptoms have resolved for at least 72 hours.

Table 2 - Neurologic Toxicity

^a Grade for ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading (Lee et al 2019).
^b If ICANS, manage as per institutional guidelines. Refer also to Crombie et. al for alternative ICANS management guidelines.
^c Anticytokine therapy is recommended if ICANS occurs concurrently with CRS. Refer to local institutional guidelines for management of concurrent CRS and ICANS.
^d Resume at dose described in Table 4.
^e Consider the type of neurologic toxicity before deciding to withhold glofitamab.

Table 3 - Other Toxicities

*Resume at dose described in Table 4.

**Especially in patients with bulky tumours located in close proximity to airways and/or vital organs.

Table 4 - Restarting After Dose Delay

Table 5 - Management of Infusion-related reactions (including CRS):

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

* Ensure symptoms are resolved for at least 72 hours prior to next infusion of glofitamab.  

The safety and efficacy of obinutuzumab have not been established in patients with hepatic impairment.

No glofitamab dose adjustment is necessary for mild hepatic impairment based on pharmacokinetic studies (no clinically significant differences observed). Glofitamab has not been studied in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and any AST). 

Patients who have a creatinine clearance < 50mL/min in the obinutuzumab pivotal studies (in combination with chemotherapy) experienced more serious adverse events, including fatal ones, than those with creatinine ≥ 50 mL/min.

No glofitamab dose adjustment is necessary in patients with mild or moderate renal impairment (CrCl 30 to < 90 mL/min). No clinically significant changes in the pharmacokinetics of glofitamab were observed based on mild to moderate renal impairment.  The effects of severe renal impairment (CrCl 15 to < 30 mL/min) and end-stage renal disease (CrCl < 15 mL/min) on the pharmacokinetics of glofitamab are unknown. 

No obinutuzumab or glofitamab dose adjustments are required in patients ≥ 65 years of age. No differences in efficacy of glofitamab or obinutuzumab were observed between older and younger patients. 

NHL patients ≥ 65 years of age experienced more serious adverse effects with obinutuzumab and chemotherapy than younger patients.

Refer to oBINutuzumab, glofitamab drug monograph(s) for additional details of adverse effects.

The table below lists the adverse effects of glofitamab only. Refer to oBINutuzumab drug monograph for adverse effects of obinutuzumab.

Refer to oBINutuzumab, glofitamab drug monograph(s) for additional details.

• Caution with obinutuzumab and drugs that cause immunosuppression (e.g. leflunomide, etanercept, clozapine, other antineoplastics); monitor closely or avoid, if possible.
• Glofitamab may cause transient suppression of CYP450 enzymes. Monitor and adjust doses of CYP450 substrates with narrow therapeutic index (e.g. warfarin, cyclosporine) as necessary.

Refer to oBINutuzumab, glofitamab drug monograph(s) for additional details.

Administration

Obinutuzumab:

• Obinutuzumab should be administered only as an IV infusion through a dedicated line.  Do not administer as an IV push or bolus.
• Infuse IV at 50 mg/h. The rate of infusion can be escalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h.
• Withdraw required amount of diluent from vial and dilute in a 250 mL bag containing 0.9% sodium chloride. See product monograph for details.
• Gently invert the IV bag to mix. Do not shake.
• Compatible with sodium chloride 0.9%. Do not mix with other IV solutions.
• Also compatible with the following IV bags and sets:
  • PVC, non-PVC polyolefin, polyethylene, polypropylene bags
  • PVC, polyurethane or polyethylene infusion sets
  • polyetherurethane catheters
  • optional inline filters with polyethersulfone product contact surfaces
  • 3-way stopcock infusion aid made from polycarbonate
• Store vials between 2° to 8°C; protect from light.

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

Glofitamab:

• Infuse IV through a dedicated line. Do NOT administer as an IV push or bolus.
• Do not mix with other drugs.
• Dilute in a 50mL or 100mL 0.9% or 0.45% sodium chloride infusion bag.
• Final drug concentration after dilution should be 0.1 mg/mL to 0.6 mg/mL.
• Gently invert infusion bag to mix. Do not shake.
• Compatible with polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), or non-PVC polyolefin 0.9% NS IV bags and PVC 0.45% sodium chloride IV bags. 
• Compatible with infusion sets with product-contacting surfaces of polyurethane, PVC, PE, and in-line filter membranes made of polyethersulfone or polysulfone
• Infuse IV over 4 hours (2.5 mg, 10mg and first 30mg dose).
• May infuse over 2 hours (Cycle 3 and onwards) if previous dose well tolerated. 
• Monitor patients during infusion, for 10 hours after the first glofitamab dose (2.5mg, Cycle 1, Day 8) and after subsequent doses as necessary, for signs and symptoms of CRS or ICANS. 
• Store unopened vials refrigerated (2°C to 8°C) and protect from light. 

Contraindications

• Patients who have a hypersensitivity to these drugs or any of their components.

Warnings / Precautions

• Obinutuzumab and glofitamab should not be given in the presence of an active infection.
• Avoid live vaccines during treatment with obinutuzumab and glofitamab. Following vaccination, do not start obinutuzumab until protective antibody titres have been reached. The safety of immunization with live vaccines during or after glofitamab treatment has not been studied. 
• Use obinutuzumab with extreme caution in patients who are positive for hepatitis
• Use caution in patients with:
  • a history of recurring or chronic infections;
  • underlying conditions that may predispose them to infections;
  • significant prior immunosuppressive treatment.
• Patients with a history of cardiovascular or respiratory disease should be monitored closely during and after obinutuzumab infusion. Use caution when hydrating patients with history of cardiovascular disease, to prevent fluid overload
• Patients at acute risk of hypertensive crisis should be assessed for the risk vs benefit of withholding anti-hypertensives. If deemed clinically appropriate, hold antihypertensive medications for 12 hours prior to, during, and for the first hour after obinutuzumab infusion.
• Serious and life-threatening CRS have occurred with glofitamab, ensure step-up schedule is followed and infusions are administered where there is immediate access to medications and equipment required to manage CRS.
• Symptoms of CRS (e.g. tachycardia, hypotension, hypoxia) or neurological effects may affect ability to drive or operate machinery. Patients should avoid driving or operating machinery until symptoms resolve.
• Patients with high tumour burden, rapidly proliferative tumours, renal dysfunction or dehydration are at greater risk of tumour lysis syndrome. 
• Patients with conditions such as central nervous system lymphoma, prior allogeneic HSCT and autoimmune disease (requiring immunosuppressive therapy) were excluded from clinical trials; assess benefit-risk of glofitamab treatment in these patients.

Pregnancy and Lactation

• This regimen is not recommended for use in pregnancy. IgG1 antibodies are known to cross placenta. 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: 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

Crombie JL, Graff T, Falchi L, et al. Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy. Blood 2024; 143 (16): 1565–1575.

Dickinson MJ, Carlo-Stella C, et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022 Dec 15;387(24):2220-31. 

Glofitamab drug monograph. Ontario Health (Cancer Care Ontario). 

Lee W, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release Syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625-38.

Obinutuzumab drug monograph. Ontario Health (Cancer Care Ontario).