CVP+OBIN

For obinutuzumab maintenance use, report as regimen OBIN(MNT) after CVP+OBIN induction.

Induction: REPEAT EVERY 21 DAYS for up to 6 cycles, unless disease progression or unacceptable toxicity (see NDFP form)

For patients who responded to or have stable disease after induction therapy, refer to maintenance obinutuzumab regimen - OBIN(MNT).

Other Supportive Care:

Obinutuzumab:

Hepatitis B screening should be performed prior to treatment for all patients.

Patients at risk for tumour lysis syndrome should receive adequate hydration and uricostatics or alternative starting 12 to 24 hours prior to infusion.

Consider withholding antihypertensives (if applicable) 12 hours prior to infusion, during infusion and for the first hour after drug administration, and withholding concomitant medications that increase bleeding risk, especially in the first cycle.

Patients with neutropenia should receive antimicrobial prophylaxis; consider use of G-CSF, antiviral and antifungal prophylaxis.

Premedication recommendations:

*e.g. 100 mg prednisone or 20 mg dexamethasone. Hydrocortisone should not be used as it has not been effective in reducing IR rates.

^ If a corticosteroid-containing chemotherapy regimen is given on the same day as obinutuzumab, the corticosteroid can be given as PO if given at least 1 hour prior to obinutuzumab, in which case additional IV corticosteroid as premedication is not required.

**e.g. 1000 mg acetaminophen

***e.g. 50 mg diphenhydramine

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 may be considered.

No dose reductions are recommended for obinutuzumab. The infusion may be discontinued, held or its rate reduced as described in the table below.

_{*Missed doses may be administered later at physician discretion; the q28 day interval should be maintained.
**Hold up to 4 weeks. Before retreatment, major organ toxicities should recover to ≤ grade 1 (or as specified in table above), platelets ≥ 100 x 10⁹/L and ANC ≥ 1.5 x 10⁹/L.}

Obinutuzumab Infusion Reactions:

For obinutuzumab, safety and efficacy have not been established in patients with hepatic impairment.

Consider dose modification for vincristine for severe increase in LFTs.

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For obinutuzumab, patients who have a creatinine clearance < 50 mL/min in the pivotal study experienced more serious adverse events, including fatal ones than those with creatinine ≥ 50 mL/min.

No dose adjustment is required. Patients ≥ 65 years experienced more serious adverse events than younger patients. No efficacy differences were observed between older and younger patients.

Refer to oBINutuzumab, vinCRIStine, cyclophosphamide drug monograph(s) for additional details of adverse effects

Refer to oBINutuzumab, vinCRIStine, cyclophosphamide drug monograph(s) for additional details

• No clinical drug interaction studies have been conducted with obinutuzumab.
• Consider withholding antihypertensives (if applicable) 12 hours prior to obintuzumab infusion, during infusion and for the first hour after drug administration, and withholding concomitant medications that increase bleeding risk, especially in the first cycle.
• Caution and monitor closely for infections when given with other immunosuppressive drugs.
• Caution with use of CYP3A4 inhibitors and cyclophosphamide; avoid grapefruit for 48 hours before and on day of cyclophosphamide
• Avoid combination of vincristine and verapamil or nifedipine; monitor closely if given concurrently
• Monitor serum phenytoin levels when used with vincristine, and adjust phenytoin dose prn

Refer to oBINutuzumab, vinCRIStine, cyclophosphamide drug monograph(s) for additional details

Administration:

obinutuzumab

_{*For infusion rate modifications in the case of IR, see dosage with toxicity section}

• Obinutuzumab should be administered only as an IV infusion through a dedicated line.  Do not administer as an IV push or bolus.
• Withdraw required amount of diluent from vial and dilute in 250 mL PVC or non-PVC polyolefin bags containing 0.9% sodium chloride. See product monograph for details.
• Gently invert the IV bag to mix. Do not shake.
• If a planned dose is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval should then be maintained between doses.
• Compatible with sodium chloride 0.9%. Do not mix with other IV solutions.
• Also compatible with the following IV bags and sets:
  • polyethylene, polypropylene bags
  • PVC, polyurethane or polyethylene infusion sets
  • polyetherurethane catheters
  • optional inline filters with polyethersulfon product contact surfaces
  • 3-way stopcock infusion aid made from polycarbonate

vinCRIStine

FOR INTRAVENOUS USE ONLY.  Vincristine is lethal if given intrathecally. No successful antidotes have been described.  Syringes containing this product should be labelled “WARNING – FOR INTRAVENOUS USE ONLY.  FATAL if given by other routes.” 

• Direct IV push not recommended, due to risk of inadvertent intrathecal administration.
• For intermittent IV use, may mix in small volume minibag (ie. 50mL NS or D5W for adults).
• Infuse IV via gravity. Infusion pumps should not be used peripherally, since they deliver infusions at higher pressures and may continue to infuse when extravasation occurs.
• During the infusion, suggest nurse to remain present with the patient to observe the IV site for extravasation.

cyclophosphamide

• Oral hydration is strongly encouraged; for PO cyclophosphamide: 8-10 (8oz) glasses of fluid per day; for IV cyclophosphamide: 2-3 L of fluid/day; poorly hydrated patients may need more IV hydration. Inadequate total hydration may result in dose-related hemorrhagic cystitis.  Patients should be encouraged to empty their bladder frequently to minimize dwell times.
• Dilute in 250mL NS and infuse over 30 minutes.
• Use sodium chloride 0.9% to reconstitute cyclophosphamide
• Do not reconstitute or dilute with benzyl alcohol-containing solutions (ie. Bacteriostatic sodium chloride), since it may catalyse the decomposition of cyclophosphamide or cause toxicity in infants
• Avoid the use of aluminium-containing preparation and administration equipment, since darkening of aluminium and gas production have been reported.

Contraindications

• Patients who have a hypersensitivity to this obinutuzumab, vincristine or other vinca alkaloids, cyclophosphamide, prednisone or any of its components.
• Patients with the demyelinating form of Charcot-Marie-Tooth Syndrome or childhood polio
• Vincristine intrathecal administration is absolutely contraindicated.
• (cyclophsphamide) patients with urinary outflow obstruction
• (cyclophosphamide) patients with adrenal insufficiency
• (cyclophosphamide) in combination with neuromuscular blockers

Precautions

• Do not give to patients who have an active infection.
• Use with extreme caution in patients who are positive for hepatitis.
• Avoid live and live-attenuated vaccines during treatment and until B-cell recovery. Following vaccination, do not start obinutuzumab until protective antibody titres have been reached.
• Reduced immunogenicity may occur with use of inactivated vaccines.
• Use with caution in patients with a history of recurring or chronic infections
• Patients with a history of cardiovascular or respiratory disease should be monitored closely during and after obinutuzumab infusions. 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 with obinutuzumab.
• Vincristine should not be given to patients who are receiving radiation that includes liver portals.
• Use vincristine with caution with other neuromuscular disorders, neurotoxic/ototoxic drugs, in leukopenia, complicating infection, or and in patients with Guillain-Barre Syndrome.

Pregnancy/lactation

• CVP+OBIN is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 18 months after the last dose. In case of exposure during pregnancy, newborns should be monitored for B-cell depletion and live vaccines postponed until B cell recovery. 
• Breastfeeding is not recommended during treatment and for at least 18 months after the last dose.
• Fertility may be affected.

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

Obinutuzumab, vincristine, cyclophosphamide drug monographs, Cancer Care Ontario.

Cheson BD, Chua N, Mayer J, et al.  Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study.  J Clin Oncol. 2018 Aug 1;36(22):2259-66.

Marcus R, Davies A, Ando K, et al.  Obinutuzumab for the first-line treatment of follicular lymphoma.  N Engl J Med 2017;377(14):1331-44.

Radford J, Davies A, Cartron G, et al.  Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000).  Blood. 2013 Aug 15;122(7):1137-43.