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CVP+OBIN

Cancer Type: Hematologic, Lymphoma - Non-Hodgkin's Low Grade  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Obinutuzumab - In Combination with Chemotherapy for Refractory Follicular Lymphoma
ODB - General Benefit
    prednisone
A - Regimen Name

CVP+OBIN Regimen
Cyclophosphamide-vinCRIStine-Prednisone-oBINnutzumab


Disease Site
Hematologic - Lymphoma - Non-Hodgkin's Low Grade

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 follicular lymphoma whose disease is refractory* to a rituximab-containing regimen and has a good performance status
 

† indolent lymphoma histologies other than follicular lymphoma (excluding CLL and mantle cell lymphoma) may be eligible for obinutuzumab funding (refer to NDFP form)
* no response to OR progression during or within 6 months after rituximab or a rituximab-containing regimen


Supplementary Public Funding

oBINutuzumab
New Drug Funding Program (Obinutuzumab - In Combination with Chemotherapy for Refractory Follicular Lymphoma)

prednisone
ODB - General Benefit (prednisone)

 
B - Drug Regimen

CVP+OBIN (induction)

Cycle 1:

oBINutuzumab
1000 mg IV Days 1, 8 and 15
prednisone

100 mg PO Daily on Days 1 to 5

(On Day 1 to be given as part of premedication before oBINutuzumab) 

vinCRIStine
1.4 mg /m² IV (maximum 2 mg) Day 1
cyclophosphamide
750 mg /m² IV Day 1


Cycles 2 to 6:

oBINutuzumab
1000 mg IV Day 1
prednisone

100 mg PO Daily on Days 1 to 5

(On Day 1 to be given as part of premedication before oBINutuzumab)

vinCRIStine
1.4 mg /m² IV (maximum 2 mg) Day 1
cyclophosphamide
750 mg /m² IV Day 1

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

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C - Cycle Frequency

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).

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate
Minimal (Days 8 and 15 of Cycle 1)

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.


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:

Treatment cycle, day

Patients

Premedication

Cycle 1, Day 1

All

IV corticosteroid*/^ completed at least 1 hr prior to infusion &

PO analgesic/antipyretic** & antihistamine*** at least 30 min prior to infusion

 

Subsequent infusions

Patients with no prior IR during previous infusion

PO analgesic/antipyretic** at least 30 min prior to infusion

 

 

Patients with grade 1 or 2 IR with previous infusion

PO analgesic/antipyretic** & antihistamine*** at least 30 min prior to infusion

 

 

Patients with grade 3 IR with previous infusion OR

patients with lymphocyte counts > 25 x 109/L prior to next treatment

IV corticosteroid*/^ completed at least 1 hr prior to infusion &

PO analgesic/antipyretic** & antihistamine*** at least 30 min prior to infusion

*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

 
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 may be considered.

Dosage with toxicity

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

 

 

 

Toxicity

Obinutuzumab dose*, **

Vincristine (% previous dose)*,** Cyclophosphamide (% previous dose)*,**

Grade 4 hematologic toxicity, febrile neutropenia or thrombocytopenic bleeding

Hold until ≤ grade 2, restart at usual dose. 

Discontinue if no recovery within 4 weeks.

 

 

 

No change

75% or GCSF for low ANC

Discontinue if no recovery within 4 weeks

Grade 2 or 3 related organ/non-hematologic toxicity

Hold until ≤grade 1.

Discontinue if no recovery within 4 weeks

100%

Grade 3:  75%

 

Neurotoxicity 100% Mild: 67%;
Moderate:  Hold until  recovery, then ↓ 50%;
Severe:  Discontinue
100%
Cystitis 100% 100% Hold until resolved

Grade 4 related organ/non-hematologic toxicity

Discontinue

Viral hepatitis or other serious infections; reactivation of hepatitis B

Discontinue

Suspected PML

Hold and refer to neurologist for diagnosis and treatment.  Discontinue if confirmed.

*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:

Toxicity Grade Obintuzumab dose
Grade 1-2 Infusion Reaction (IR)

Reduce infusion rate and treat symptoms.

Restart once resolved. Escalate infusion rate as tolerated at increments appropriate for treatment dose (see table in Drug Administration section).

Grade 3 IR

Hold infusion and treat symptoms.

Restart once resolved at no more than half the previous rate. Escalate infusion rate as tolerated at increments appropriate for treatment dose (see table in Drug Administration section).

Grade 4 IR,

2nd episode of grade 3 IR (during same or subsequent infusion),

acute life-threatening respiratory symptoms

or Anaphylaxis / serum sickness

Discontinue



Hepatic Impairment

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

Consider dose modification for vincristine for severe increase in LFTs.

(Continued on next page)

 

 

Bilirubin

Vincristine
(% previous dose)

Cyclophosphamide
(% previous dose)

Obinutuzumab

1 – 2 X ULN

50%

100%

No data
 

2 – 4 x ULN

25%

Caution

> 4 ULN

OMIT

Caution


Renal Impairment

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.

Creatinine clearance (mL/min)
Obinutuzumab dose
Cyclophosphamide dose Vincristine dose
> 50
No dose adjustment
100% No dose adjustment required
30-50
No dose adjustment; use with caution
75%
10-29
No data
<10 Use with extreme caution or discontinue

Dosage in the Elderly

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.

 


 
F - Adverse Effects

Refer to oBINutuzumab, vinCRIStine, cyclophosphamide 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, vomiting
  • Infusion-related reaction (immediate or delayed; may be severe)
  • Myelosuppression +/- infection (including atypical, viral reactivation), bleeding (may be severe
  • Increased LFTs (may be severe)
  • Increased creatinine (may be severe)
  • Fatigue
  • Flu-like symptoms
  • Constipation
  • Diarrhea
  • Abdominal pain
  • Anorexia
  • Rash (may be severe)
  • Musculoskeletal pain
  • Headache
  • Insomnia
  • Alopecia
  • Cough, dyspnea
  • Steroid effects
  • Peripheral neuropathy
  • Mucositis
  • Cystitis
  • Fever
  • Arterial / venous thromboembolism
  • Cardiotoxicity
  • Arrhythmia
  • QT prolongation
  • GI perforation
  • Tumour lysis syndrome
  • Secondary malignancy
  • SIADH
  • Autonomic or cranial neuropathy
  • PML
  • Hemolysis
  • Capillary leak syndrome
  • Pancreatitis
  • Pneumonitis
  • VOD
  • Anaphylaxis, serum sickness

 

 
G - Interactions

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
 
H - Drug Administration and Special Precautions

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


Administration:

obinutuzumab

Treatment cycle

Obinutuzumab  dose

Infusion rate*

Cycle 1, day 1

1000 mg

50 mg/hr. May escalate as tolerated by 50 mg/hr q30 min to max of 400 mg/hr.

Cycle 1, days 8 & 15;

Cycles 2-6, day 1

1000 mg

100 mg/hr if IR ≤ grade 1 at rates ≥ 100mg/hr on day 1. May escalate as tolerated by 100 mg/hr q30 min to max of 400 mg/hr.

50 mg/hr if previous grade grade 2 or 3 IR. May escalate as tolerated by 50 mg/hr q30 min to max of 400 mg/hr.

*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.
 
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, before each visit and as clinically indicated following treatment completion
  • Liver function tests; Baseline and at each cycle
  • Renal function tests and electrolytes; Baseline and at each cycle
  • Cardiac tests for all patients with cardiac risk factors; Baseline and as clinically indicated
  • Hepatitis B screening prior to treatment for all patients. Monitor for signs and symptoms of hepatitis B during treatment. Seropositive patients should see hepatologist and be closely monitored for several months after the last infusion.
  • Infusion-related reactions; During and after each infusion
  • Clinical toxicity assessment for tumour lysis syndrome, infection, bleeding, injection site reactions, thromboembolism, GI, hypersensitivity, neurotoxicity, cystitis, skin, pulmonary and cardiac symptoms; At each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
4 hours
Pharmacy Workload (average time per visit)
37.887 minutes
Nursing Workload (average time per visit)
84.833 minutes
 
K - References

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.

May 2019 Updated emetic risk category


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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.