Summary Basis of Decision for Zevalin ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Zevalin®
Ibritumomab tiuxetan, 3.2 mg/2 mL, Solution
Kit for the preparation of 90Y Ibritumomab tiuxetan
Berlex Canada Inc.
Submission control no: 076192
Date issued: 2006-06-23
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), ZEVALIN®, Ibritumomab tiuxétan, 3.2 mg/2 mL, solution, Berlex Canada Inc., N° de contrôle de la présentation 076192
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
90Y Yttrium Chlori
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- N/A
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
® Berlex Canada Inc.
2 Notice of decision
On May 10, 2005 , Health Canada issued a Notice of Compliance to Berlex Canada Inc. for the drug product Zevalin, a therapeutic radiopharmaceutical. Zevalin contains the medicinal ingredient ibritumomab tiuxetan that is radiolabelled with Yttrium-90 (90Y).
Zevalin is indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma, including patients with rituximab-refractory follicular non-Hodgkin's lymphoma. Zevalin is composed of the murine monoclonal antibody ibritumomab that is linked to the chelator tiuxetan, which binds the 90Y radioisotope. Ibritumomab is a murine IgG1 monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. When administered intravenously, Zevalin selectively targets tumour cells with the delivery of the radiation dose resulting in significant tumour shrinkage.
This submission was granted Priority Review due to the unmet medical need for an innovative therapy in the treatment of non-Hodgkin's lymphoma.
The market authorization for Zevalin was based on satisfactory review of quality (chemistry and manufacturing), non-clinical, and clinical data. The safety and efficacy of the Zevalin therapeutic regimen were evaluated in two multi-centre trials enrolling a total of 197 subjects. Patients treated with Zevalin exhibited adequate evidence of efficacy for the authorized indication. The data submitted demonstrate that Zevalin can be administered safely when used under the conditions stated in the Product Monograph.
Zevalin (3.2 mg/2 mL ibritumomab tiuxetan) is supplied as a kit that contains all of the non-radioactive components necessary to prepare a single dose of Zevalin for labelling with 90Y for intravenous use. The therapeutic regimen of Zevalin is administered in a two step process. Step 1 includes a single infusion of rituximab. Step 2 is initiated seven to nine days following step 1 and consists of a second infusion of rituximab followed by 90Y-Zevalin. Dosing guidelines are available in the Product Monograph.
Zevalin is contraindicated for patients with known hypersensitivity to ibritumomab tiuxetan, to Yttrium (90Y) chloride, to other murine proteins or to any component of the Zevalin regimen. Detailed conditions for the use of Zevalin are available in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Zevalin is favourable for the treatment of patients with relapsed or refractory low-grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma, including patients with rituximab-refractory follicular non-Hodgkin's lymphoma.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (medicinal ingredient)
Description
Ibritumomab tiuxetan, the active ingredient of Zevalin is composed of the murine monoclonal antibody ibritumomab that is linked to the chelator tiuxetan, which binds the 90Y radioisotope. Ibritumomab is a murine IgG1 monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. When administered intravenously, Zevalin (90Y ibritumomab tiuxetan) selectively targets tumour cells with the delivery of a localized radiation dose resulting in significant tumour shrinkage.
Manufacturing Process and Process Controls
The monoclonal antibody ibritumomab is produced by genetically engineered Chinese hamster ovary (CHO) cells. The manufacture of ibritumomab is based on a CHO master cell bank system, which has been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines.
The manufacture of ibritumomab comprises a series of steps which include fermentation, harvest and purification. The purification is performed via a combination of chromatographic and viral inactivation/removal steps. The method of manufacturing and the controls used during manufacturing are validated based on the production of three consistency lots. Each lot met the specifications for drug substance production. The antibody ibritumomab is then conjugated with tiuxetan to create ibritumomab tiuxetan (conjugated antibody). In-process controls performed during the manufacture and conjugation process were reviewed and considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterisation studies were performed to provide assurance that ibritumomab tiuxetan is consistently exhibiting the desired characteristic structure. The tests are adequately controlling the levels of product and process-related impurities. Genetic characterisation analysis (nucleotide sequence and Southern blot analysis) also demonstrated stability of the Master Cell Bank (MCB).
Results from the process validation studies indicate that the methods used during processing are sufficient to detect and measure product-related and process-related impurities. The impurities that were reported and characterized were found to be within ICH established limits.
Control of Drug Substance
Validation reports were satisfactorily submitted for all analytical methods applied to the antibody and the conjugated antibody. The drug substance specifications, and analytical methods used for quality control of ibritumomab/ibritumomab tiuxetan are considered acceptable.
Data from the batch chosen to serve as a suitable reference standard and from the three consistency batches were considered acceptable according to the drug substance specifications established for the identity, composition, potency and purity of ibritumomab and ibritumomab tiuxetan.
Stability
Based upon stability studies conducted, in accordance with ICH guidelines, the suggested shelf-life, storage, and shipping conditions for the drug substance are supported and considered to be appropriate.
3.1.2 Drug Product
Description and Composition
Zevalin (ibritumomab tiuxetan) is a clear, colorless sterile solution supplied in a kit ready for radiolabelling with Yttrium-90 [90Y]. In addition to the medicinal ingredient ibritumomab tiuxetan, the Zevalin kit consists of 3 non-radioactive components necessary to prepare a single-unit dose of 90Y ibritumomab tiuxetan for therapeutic administration (intravenous infusion). The container closure system is the same for all 4 components and consists of a clear Type I glass vial sealed with a grey rubber stopper and crimped with an aluminum seal fitted with a different coloured flip-off cap.
The kit for the preparation of 90Y-Zevalin contains:
- 1 vial containing 3.2 mg of ibritumomab tiuxetan in 2 mL of normal saline solution supplied as a clear, colorless solution that may contain translucent particles
- 1 vial of 50 mM sodium acetate containing 13.6 mg of sodium acetate trihydrate in 2 mL of water for injection supplied as a clear, colorless solution
- 1 vial of formulation buffer containing 750 mg of human serum albumin, 76 mg of sodium chloride, 21 mg of sodium phosphate dibasic dodecahydrate, 4 mg of pentetic acid, 2 mg of potassium phosphate monobasic and 2 mg of potassium chloride in 10 mL of water for injection supplied as a yellow to amber coloured solution
- 1 empty reaction vial
- 4 identification labels
The radioisotope Yttrium-90 [90Y] chloride is not included as part of the kit but is shipped directly from the manufacturer upon placement of an order for Zevalin.
Pharmaceutical Development
During the pharmaceutical development of Zevalin, no changes were made to the composition of the intended commercial product, except for the formulation buffer component which underwent two minor changes to conform to pharmacopoeial monographs. Data reviewed regarding implemented changes confirmed that the integrity and specificity of the antibody remained unaffected.
As for the manufacturing process of the intended commercial product, the means of manufacturing ibritumomab were changed during development. Data pertaining to physicochemical characteristics and biological activity demonstrated biocomparability between development and commercial batches.
Manufacturing Process and Process Controls
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters are adequately described in the submitted documentation and are found acceptable. Ibritumomab tiuxetan is transferred into vials using adequate aseptic process techniques utilizing conventional pharmaceutical equipment and facilities.
The selected formulation retains full potency, purity and protein integrity of ibritumomab tiuxetan during the proposed shelf-life. All excipients used in the Zevalin kit comply with either the US Pharmacopoeia (USP) or the European Pharmacopoeia (Ph. Eur.).
Control of Drug Product/Kit
Zevalin, the drug product and the kit components, have been tested for the required quality as per respective specifications. Among other parameters, it is tested for physical appearance, protein concentration, identity, purity, sterility, potency, stability, bacterial endotoxins, and presence of viral contaminants during manufacturing. The validation reports submitted for all analytical procedures used for in-process and batch release testing are satisfactory and in compliance with ICH guidelines.
Batch analyses data were reviewed and considered to be acceptable since the results met the specifications of the drug product and other components of the kit.
Stability
Stability data support a shelf-life of 36 months for the ibritumomab tiuxetan drug product when stored at the recommended temperature of 2-8°C. A shelf-life of 8 hours for the radiolabelled ibritumomab tiuxetan is recommended. However, it is suggested to use the product immediately after radiolabelling.
The shelf-life of the kit is based on the expiry of the kit component that has the shortest shelf-life.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production and quality control are considered suitable for their respective activities. All facilities are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Pre-harvest cell culture fluid from each lot is tested to ensure freedom of adventitious microorganisms (bacteria, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses were adequately validated. No excipients of animal/human origin are used during the manufacture of ibritumomab tiuxetan drug product, except for human serum albumin (HSA) which is included in the formulation buffer. The source and quality of the HSA is approved by Health Canada.
All excipients supplied in the Zevalin kit meet the compendial requirements of EP/USP.
3.1.5 Summary and Conclusion
This New Drug Submission for Zevalin has undergone a thorough Quality review and was found to comply with the requirements of Section C.08.002 of the Food and Drug Regulations.
The Chemistry and Manufacturing information submitted for Zevalin has demonstrated that the drug substance and drug product can be consistently manufactured to meet specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for release of commercial batches.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
In vitro studies
Several assays and immunohistochemistry studies were used to demonstrate the equivalent binding of CHO derived antibody when compared to the hybridoma produced antibody. In addition, tests were performed to demonstrate that coupling tiuxetan to ibritumomab did not alter the binding characteristics of the antibody preparation. Results from in vitro studies conducted support the following conclusions:
- Immunohistochemical analysis of tissue distribution of CHO-produced ibritumomab-tiuxetan with the Yttrium-89-mock labelled conjugate demonstrated a restricted pattern of distribution, mainly found on a subset of lymphoid cells. Epithelial cells of different organs, mesenchymal elements and neuroectodermal cells were found to be non-reactive.
- Ibritumomab did not bind specifically to either rat or mouse B-cells, thus precluding the use of these models for safety and pharmacokinetic studies.
- The murine monoclonal antibody ibritumomab was shown to bind to
CD20-antigen with high specificity. When the antibody was conjugated to tiuxetan, no reduction in the specific binding was demonstrated. The antibody-conjugate demonstrated equivalence to Coulter B1 anti-CD20 antibody and both reacted with the antigen with a very restricted pattern of distribution limited to a subset of lymphoid cells.
In vivo studies
Ibritumomab tiuxetan was studied in athymic mice bearing human B-cell lymphomas to assess its antiproliferative effects , and to determine the tumour accumulation of the antibody conjugate. Results showed the following:
- Studies with Yttrium-labelled ibritumomab tiuxetan in Ramos xenografts models demonstrated that [90Y] labelled ibritumomab tiuxetan and the chimeric rituximab exhibited comparable tumouricidal effect. The combination of both therapeutic reagents did not demonstrate additive nor synergistic effects.
- In two biodistribution studies, relatively high levels of radiolabelled antibody were recovered in the tumour tissue following intravenous administration. This time-dependent increase of radioactivity in the tumour tissues demonstrated the selective uptake of the conjugate by the CD20+ tumour cells. In contrast, blood and most tissue levels of radiolabelled antibody decreased throughout the observation period.
Further studies with ibritumomab and its conjugate in animals have been limited to cynomolgus monkey because of the known reactivity of ibritumomab and its chimeric analog rituximab with primate B-cells.
3.2.2 Pharmacokinetics
Data obtained from animal pharmacokinetic studies demonstrated the following:
- Biodistribution with intravenous radiolabelled and conjugated antibody demonstrated that the human radiation doses were similar across studies with acceptable radiation to normal human tissues and limited levels of skeletal and marrow radiation.
- Radiolabels obtained from two different supplying manufacturers demonstrated similar biodistribution independent of the supplier. Similarily, the pharmacokinetics of two ibritumomab tiuxetan lots produced at the two different manufacturing sites were identical. This indicates that the antibody conjugates were stable in vivo and that either may be used for therapeutic production.
- Biliary excretion was the predominant excretion pathway after administration of [111In] ibritumomab tiuxetan (37% of the dose) and of [90Y] labelled ibritumomab tiuxetan (48% of the dose). Similar dose fractions were excreted in feces and urine.
- In pharmacokinetic studies in mice, the serum half-life (T1/2) of ibritumomab and ibritumomab tiuxetan was approximately 8.75 days after a single intravenous dose of 0.025 mg/mouse. In rats, a single intravenous bolus administration of 3.2 mg/kg of ibritumomab tiuxetan resulted in an average maximum serum concentration (Cmax) of 60-67 μg/mL, an average AUC of 395 to 415 μg*d/mL and a T1/2 of 11 days. In cynomolgus monkeys, the T1/2 of ibritumomab was 4.5 days after a single infusion of 10 mg/kg.
- Toxicokinetic examinations in cynomolgus monkeys with administration of [89Y] labelled ibritumomab tiuxetan alone or in combination with rituximab on day 1 and day 8 revealed that higher plasma concentrations of [89Y] ibritumomab tiuxetan were achieved after combination of the two compounds. Similarly, the half-life of [89Y] ibritumomab tiuxetan was longer (74 versus 17 hours) and the AUC value and mean residence times were significantly higher in animals treated with rituximab and [89Y] labelled ibritumomab tiuxetan than in animals treated with [89Y] labelled ibritumomab tiuxetan alone.
3.2.3 Toxicology
Animal toxicology studies evaluated single- and repeat-dose toxicity of Zevalin. Toxicology evaluation of ibritumomab and its conjugate were limited to cynomolgus monkey because of the known reactivity of ibritumomab and its chimeric analog rituximab with primate B-cells. Canine B-cells lack a binding activity for ibritumomab or its chimeric analog rituximab. Mice and rats were not used because murine antibody would not react with murine or rat CD20 cells.
Single-Dose Toxicity
A single intravenous dose of 10 mg/kg of ibritumomab (160 times the human dosage) was administered to evaluate the half-life of the drug. Parameters such as clinical observations, physical examination, body temperature, food consumption, body weight, urinalysis, hematological and chemical tests, and immunological markers of circulating lymphocytes were monitored. The drug was tolerated without unexpected adverse effect. The only finding was a reversible depletion of the circulating B-cells. T-cell population was not affected. The depletion of circulating B-cells is of little relevance since in clinical use, they are eliminated by pre-treatment with rituximab.
Repeat-dose toxicity
Repeated doses (7 administrations over 13 days) with ibritumomab and its [89Y] labelled conjugate ibritumomab tiuxetan (160 times therapeutic dose in patients) alone or in combination with rituximab (equivalent to human dose) did not result in any adverse effect. The main finding was a reversible depletion of the circulating and/or tissue B-cells, which is the targeted effect of the rituximab pre-treatment. T-cells, or other white blood cells, remained unaffected.
Carcinogenicity
Carcinogenicity studies were not conducted, as ibritumomab tiuxetan is only intended for short-term use and has no structural similarities to carcinogens. However, treatment with radiolabelled compounds is known to have a carcinogenic potential due to exposure to ionizing radiation. Taking into account the radiation dose estimates for normal human tissue as well as the single use of the [90Y] labelled antibody in patients, the risk is considered to be acceptable.
Mutagenicit
Mutagenicity studies were not performed as they are not applicable for products derived from biotechnology processes. Due to exposure to ionizing radiation, a possible mutagenic risk has to be considered. Taking into account the results of biodistribution in mice and estimated radiation dose to normal tissues, the risk is acceptable.
Reproductive and developmental toxicity
Studies on reproductive and developmental toxicity and studies on the mutagenic potential were not performed, as they were not necessary for this type of compound. It is not known whether ibritumomab tiuxetan passes the placenta. However, due to the potential risk of exposure of the fetus to ionizing radiation, or to the antibody, Zevalin should not be used during pregnancy. It is recommended to exclude women during pregnancy and men and women of childbearing potential should use contraceptive measures during treatment and for 12 months afterwards. It is not known whether ibritumomab tiuxetan is excreted in milk. Given that human IgG is excreted in human milk and that there is the potential for immunosuppression in the infant, women are advised to discontinue nursing until circulating drug levels are no longer detectable.
3.2.4 Summary and Conclusion
Preclinical animal studies performed were adequate and provided useful information regarding antibody production, specificity and cytotoxic mechanism of action. Ibritumomab was developed using standard hybridoma techniques. The antibody was also shown to have specific binding to CD20+ B-cells with no reaction to other types of lymphocytes, T-cells, monocytes and macrophages.
Single and repeated doses of ibritumomab and its [89Y] labelled conjugate ibritumomab tiuxetan given at 160 times the human dosage were tolerated without unexpected adverse effects. The only finding was reversible depletion of circulating B-cells. T-cells remained unaffected.
Carcinogenicity, mutagenicity and reproductive teratology studies were not performed as they are generally not applicable for this type of compound. It is recognized that radiolabelled compounds with ionizing radiation can represent a risk. Taking into account the results of biodistribution studies in mice and radiation doses absorbed by normal tissues, the risk is deemed acceptable.
It is not known whether Zevalin passes the placenta. Due to the possible risk to the fetus from exposure to ionizing radiation or to the antibody, it is recommended to exclude women from treatment during pregnancy and men and women of childbearing potential should use contraceptive measures during treatment and for 12 months afterwards. Because human IgG is excreted in human milk, women are advised to discontinue nursing until circulating drug levels are no longer detectable.
3.3 Clinical basis for decision
3.3.1 Clinical Pharmacology Program
| Protocol | Design and Objective | Enrolment | Treatment |
|---|---|---|---|
| 106-04 [A00007] Pivotal Trial | Phase III, multicentre, randomized, active controlled, open label, fixed dose, comparative trial. To evaluate the efficacy and safety of ibritumomab radioimmunotherapy compared to rituximab immunotherapy of relapsed or refractory low grade or follicular or transformed B cell non Hodgkin's lymphoma. | 143 patients enrolled (73 treated with [90Y] Zevalin, 70 treated with rituximab). | Group 1: Day 1: Infusion with rituximab (250 mg/m2) followed by an imaging dose: IV injection of 5 mCi [111In] Zevalin. Day 7, 8 or 9: Infusion with rituximab (250 mg/m2), followed by therapeutic dose: IV injection of 0.4 mCi/kg [90Y] Zevalin (max. 32 mCi). Group 2: Infusion of 375 mg/m2 rituximab once every week for 4 weeks. |
| 106-06 [A00006] Pivotal Trial | Phase III, multicentre, non randomized within patient controlled, open label, fixed dose trial. To evaluate the efficacy and safety of ibritumomab radio immunotherapy in patients with B cell non Hodgkin's lymphoma who are refractory to prior rituximab therapy. | 57 patients enrolled (54 with follicular non Hodgkin's lymphoma). | Day 1: Infusion with rituximab (250 mg/m2).[28 of 57 patients received an imaging dose: IV injection of 5 mCi [111In] Zevalin. This dosimetry requirement was removed from the protocol for the remaining patients]. Seven days later, infusion with rituximab (250 mg/m2) immediately followed by therapeutic dose: IV injection of 0.4 mCi/kg [90Y] Zevalin. |
| 106 01 [A00004] Non Pivotal Trial | Phase 1, open label, ascending single dose escalation trial. To evaluate the treatment of B cell lymphoma with[90Y] labelled Pan B monoclonal antibody with peripheral stem cell or autologous bone marrow transplantation. | 17 patients enrolled (14 received [90Y] Zevalin, 1 received [111In] Zevalin only, and 2 received both [111In] Zevalin and ibritumomab). | Pre infusion with ibritumomab (0, 0.1, or 2.5 mg/kg) followed by an imaging dose: IV injection of 5 mCi [111In] Zevalin. Two to three weeks later, patients then received ibritumomab (1 or 2.5 mg/kg) followed by [90Y] Zevalin in escalating therapeutic doses (20, 30, 40 or 50 mCi). |
| 106-03 [A00009, A00010] Non Pivotal Trial | Phase 1, open label, ascending single dose escalation trial. Phase II, open label, fixed dose, single arm trial. To evaluate the safety and clinical activity of ibritumomab administered to patients with B cell lymphoma. | 58 patients enrolled; 50 patients received [90Y]-Zevalin, 6 received only [111Y]- Zevalin, 2 received no treatment | Group 1: Two once weekly doses of either 100 or 250 mg/m2 rituximab followed by two imaging doses of 5 mCi [111In] Zevalin. Patients then received a therapeutic course of four, once weekly doses of 375 mg/m2 rituximab. Group 2/3: One 250 mg/m2 dose of rituximab followed immediately by a single dose of [111In] Zevalin for imaging. One week later, patients received the same dose of rituximab and a single, weight adjusted therapeutic dose of either 0.2, 0.3 or 0.4 mCi/kg [90Y] Zevalin. The standard dose of 0.4 mCi/kg was chosen for Group 3, however patients with mild thrombocytopenia were given a reduced dose of 0.3 mCi/kg. |
| 106-05 [A00005] Non Pivotal Trial | Phase II, multicentre, open label, fixed dose, single arm trial. To evaluate the safety and efficacy of ibritumomab radioimmunotherapy of relapsed or refractory low grade or follicular B cell non Hodgkin's lymphoma in patients with mild thrombo cytopenia. | 30 patients enrolled. | Day 1: Infusion with rituximab (250 mg/m2) followed by an imaging dose: IV injection of 5 mCi [111In] Zevalin. Day 8: Infusion with rituximab (250 mg/m2) followed by a therapeutic dose: IV injection of 0.3 mCi/kg [90Y] Zevalin. |
The clinical program consisted of five clinical trials in which patients with B cell non Hodgkin's lymphoma were treated with 90Y-Zevalin. Studies 106-04 and 106-06 consist of two pivotal trials. Studies 106-01, 106-03 and 106-05 were non-pivotal trials comprised of two phase I/II dose seeking studies and a phase II study in patients with mild thrombocytopenia. All studies were performed in accordance to Good Clinical Practice (GCP).
A total of 305 were enrolled in these trials, of which 226 were treated with 90Y-Zevalin, 70 were treated with rituximab as a reference therapy, and 10 were assigned to receive [111In] Zevalin, with or without unlabelled ibritumomab tiuxetan or rituximab, in early dosimetry studies. Of the 226 patients treated with 90Y-Zevalin , 211 received pre-infusions with rituximab followed by a single weight-adjusted dose of 90Y-Zevalin .
3.3.2 Pharmacodynamics
Based on the five clinical trials, results of the pharmacodynamic analyses support the following conclusions:
- B-cell depletion within 6 months after therapy and normalization by 9 months. No effect was noted on T-cells, monocytes or natural killer (NK) cells.
- IgG and IgA levels remained within normal range. IgM levels fell slightly below normal range.
- Human anti-mouse antibody and human anti-chimeric antibody reactions were very low occurring in 2.4% and 1.4% of cases, respectively. These observations were of no clinical significance.
Note that these tests were performed within 12 weeks from start of therapy. Given that research reports indicate that antibody formation could appear after 6-12 months from start of therapy, it would have been worthy to assess antibody measurements over a longer period of time following initiation of therapy.
3.3.3 Pharmacokinetics
The results of the pharmacokinetic analyses support the following conclusions:
- Depletion of CD20+ binding sites in circulating lymphocytes and in normal tissues was achieved by infusion of rituximab prior to the imaging and to the therapeutic doses of Zevalin. Though the two doses of rituximab tested (100 mg/m2 and 250 mg/m2) were equivalent, the 250 mg dose was selected in view of its potential higher therapeutic effect.
- The estimation of absorbed radiation confirmed the safety of the radiation dose delivered to marrow and normal organs (below the protocol specified upper limits) at the recommended dose. The data demonstrated lack of correlation between radiation dose to the marrow and hematologic toxicity, and that individual patient dosimetry was not necessary to ensure safety and efficacy of radiolabelled Zevalin.
- Dose adjustment by weight and hematological baseline levels are more reliable and the exclusion of patients with significant marrow involvement and prior radiation and stem cell support is more appropriate.
3.3.4 Clinical Efficacy
Five studies were submitted to support the use of Zevalin for the treatment of patients with rituximab‑relapsed or refractory CD20+ follicular B-cell non-Hodgkin's lymphoma. Their design descriptions can be found in Section 3.3.1 Clinical Pharmacology Program. Efficacy and tolerance data reviewed are based upon these five clinical trials which consist of two pivotal studies 106-04 and 106-06, and three non-pivotal trials 106-01, 106-03, and 106-05.
The pivotal trial 106-04 is a Phase III randomized study comparing Zevalin to rituximab in patients with relapsed or refractory, low grade or follicular or transformed B-cell non-Hodgkin's lymphoma. The second pivotal trial, 106-06, is a Phase III non-randomized study of Zevalin in patients with follicular B-cell non-Hodgkin's lymphoma who are refractory to prior rituximab therapy. This study is labelled as phase III as it compares responses in each patient to prior chemotherapy and prior rituximab.
The primary end-point in both pivotal studies was overall response rate and study 106-04 (randomized study) was adequately powered to detect a difference of 25%. In the 106-06 study (non-randomized), the target overall response rate was 35% and response duration was 5 months. The secondary endpoints were time to progression, duration of response, time to next cancer therapy and quality of life. The study was not powered to detect a statistical significance in time to progression but rather clinical equivalence to the control arm that was defined as a difference in 1.5 months or less between the two arms of the study.
In the 106-04 study, the primary endpoint of significant improvement in overall response rate and secondary end-points of equivalence in time to progression were reached. With regards to overall response rate, this was significant in the whole group and in the follicular subgroup. The small patient numbers in the non-follicular and transformed lymphoma groups precluded the determination of statistical significance. It is not evident therefore whether the treatment is effective in the latter two groups. This is particularly important in the transformed subgroup that has a more aggressive clinical course. Therefore more evidence of efficacy will be needed to approve an indication in the transformed lymphomas.With regards to time to progression, the study was not powered to detect a statistical difference, although there was a trend of benefit in the follicular lymphomas. Usually in cancer, clinical study efficacy is based on demonstration of benefit in overall survival, time to progression, overall response rates and quality of life. In refractory low-grade non-Hodgkin's lymphomas, it is unlikely that available therapies would demonstrate a significant survival advantage. In addition to the clear benefit in overall response rate, a significant benefit in time to progression would have further confirmed the clinical efficacy of Zevalin. However, taking into consideration the clinical setting of refractory patients with bulky disease, the benefits demonstrated in overall response rate and symptom improvement are quite convincing. Nevertheless, additional data to confirm a significant benefit in time to progression by treating an additional number of patients to provide statistical power would be desirable in the post-marketing phase.
In the 106-06 study, efficacy endpoints were also reached with evidence of efficacy beyond the targeted response rates and response duration.
The third non-pivotal study 106-05, also important, evaluated a lower dose of Zevalin in patients with mild thrombocytopenia at baseline. In this study, efficacy was similar to other studies and toxicity was slightly worse but manageable. The study also demonstrated the possibility of achieving clinical benefits with the lower dose of Zevalin and confirmed the importance of platelet levels in the prediction of toxicity and dose-adjustment without the need for individual patient dosimetry.
In conclusion, 90Y-Zevalin demonstrated a statistically significant overall response rate compared to rituximab in the treatment of follicular non-Hodgkin's lymphoma. This observed difference is long lasting, and can still be seen 6, 9, and 12 months after treatment initiation. The clinical benefit of Zevalin was also demonstrated in patients who were refractory to prior rituximab therapy. These clinical benefits were demonstrated particularly in the context of refractory heavily pre-treated patients with B-cell non-Hodgkin's lymphomas. A benefit was also shown in patients with bulky disease. The higher activity of 90Y-Zevalin defines an appropriate role in the palliative treatment of follicular lymphoma.
Dose-finding studies
The treatment regimen and doses tested in the therapeutic trials and recommended in this submission are based upon two dose-finding phase I/II studies 106-01 and 106-03. These studies were designed to determine the maximum tolerated dose of 90Y-Zevalin under conditions of optimal biodistribution.
Data from these studies established that pre-infusion of unlabelled antibody specific to the CD20 antigen led to improved biodistribution of radiolabelled Zevalin and depletion of CD20 binding sites in normal tissues. They also determined the maximum tolerated dose of Zevalin at 50 mCi. Data also demonstrated a reliable correlation between toxicity and baseline platelet levels, and confirmed the value of weight-adjusted doses of 90Y-Zevalin with a recommended dose of 0.4 mCi/kg body weight (up to a maximum of 32 mCi). In both trials, responses were observed at all doses. Based on these studies, the recommended two-step regimen schedule as detailed in the Product Monograph was established.
3.3.5 Clinical Safety
The integrated safety summary consists of data from 211 patients enrolled in four clinical trials (106-04, 106-06, 106-05 and 106-03) treated with 90Y-Zevalin at the recommended dose (i.e. pre-infusion with rituximab at 250 mg/m2 followed by injection of 90Y-Zevalin at 0.4 mCi/kg for patients with normal hematologic counts, or 0.3 mCi/kg for patients with mild thrombocytopenia). For further information on the study designs, see Section 3.3.1 Clinical Pharmacology Program.
Serious adverse events
A total of 37 patients (17.5%) of the 211 patients experienced one or more serious adverse events. These events consisted of anemia, leukopenia, thrombocytopenia, neutropenia, febrile neutropenia, urinary tract infection, bruising, deep thrombophlebitis, subdural hematoma, cellulitis, diarrhea, lung disorder, and myocardial ischemia.
Common adverse events
During the treatment period, the most frequently reported events related to treatment with 90Y-Zevalin affecting from 19 to 39% of patients were: fever, chills, nausea, and asthenia. Analysis of the safety data demonstrated that the main adverse events related to Zevalin were primarily hematological in nature.
Non-hematological toxicity
The treatment regimen of rituximab pre-infusions followed by the single 90Y-Zevalin injection led to reactions known to be associated with rituximab treatment alone, and a comparison of clinical adverse event frequencies between 90Y-Zevalin and rituximab groups in the phase III trial 106-04 revealed that only nausea, vomiting, and ecchymosis occurred more frequently with 90Y-Zevalin treatment. Non-hematological toxicities associated with Zevalin therapy were mainly grade 1 and 2 and included fatigue, abdominal pain, dizziness, headaches, nausea, chills, and fever. Of note, was the lack of toxicities such as hair loss, severe stomatitis and persistent nausea and vomiting seen in traditional combination chemotherapies.
Haematological Toxicity
Hematological toxicity was dose-limiting, and is the basis of contraindications and precautions in the use of 90Y-Zevalin. Hematological toxicity is due to the exposure of the marrow to the radioisotope; a characteristic feature of radioimmunotherapy as well as the therapeutic use of unconjugated radioisotopes.
The most important features of hematological toxicity and associated clinical sequelae can be summarized as follows:
- Hematological toxicity is manifested mainly by neutropenia and thrombocytopenia. Absolute granulocyte counts and platelet nadirs (lowest white blood cell count measured between chemotherpay treatments) occurred approximately 40-60 days after 90Y-Zevalin treatment, considerably later than would be expected with myelosuppressive chemotherapy. Differentiation of stem cells to mature granulocytes or platelets normally requires approximately 40-60 days, and nadirs occurring at this time after treatment are suggestive of stem cell effect.
- The median time to recovery from grade 4 neutropenia (14 days) or thrombocytopenia (21 days) with 90Y-Zevalin is not substantially longer than that observed in this patient population after treatment with chemotherapy. Hematopoeitic growth factor treatment was given to 36 of the 211 patients (17.1%), 13% were given G-CSF, 18.5% received red cell transfusions, and 22.3% received platelets transfusion. Stem cell support was not required for any patients outside of Phase I ascending dose trials.
- In view of the possibility of stem cell toxicity and its potential effects on the tolerability of further therapy, patients were followed up after relapse to determine the outcome of subsequent therapy, including high-dose therapy with stem cell support. Of the 211 patients assigned to 90Y-Zevalin therapy, 139 patients received subsequent chemotherapy when relapsed following Zevalin therapy. In 40 patients, where response data were available, 50 % responded to various types of chemotherapy. Ten patients underwent bone marrow transplantation (9 autologous and 1 allogeneic), 6 of the patients had their stem cells harvested after Zevalin therapy. In all cases stem cell harvesting was effective indicating that Zevalin therapy did not compromise a patient's ability to tolerate the administration of further combination chemotherapy or intensive therapy following relapse.
- Prolonged grade 4 neutropenia is usually associated with a high rate of infections or neutropenic fever. In the Zevalin clinical trials, however, the overall incidence of infections among the 211 patients analyzed for safety was 37%, of which 4.7% were grade 3 or 4 , and infection led to hospitalization in 16 (7.6%) patients. Culture-negative neutropenic sepsis was reported for 3 (1.4%) patients, and two cases were complicated by the presence of an indwelling catheter, or biliary drainage tube. These rates of infections are lower than may be expected in association with severe neutropenia. This is likely explained by the low indicidence of gastrointestional toxicity and bowel mucosa compromise observed with 90Y-Zevalin.
- Statistical tests were conducted to indentify the role of factors such as bone marrow involvement, extensive prior chemotherapy, and baseline thrombocytopenia or neutropenia in hematological toxicity. Of all factors examined, only baseline thrombocytopenia consistently and significantly correlated with nadir platelet counts or with the occurrence of grade 4 neutropenia or thrombocytopenia.
- 90Y-Zevalin treatment was well tolerated by patients with mild thrombocytopenia at 0.3 mCi/kg. The incidence of overall infection, grade 3 and 4 infection, hospitalization, and treatment-related death (none in study 106-05) was similar for all patients analyzed suggesting that the higher incidence of hematologic toxicity did not translate into a greater number of clinically significant events.
Human anti-mouse antibody and human anti-chimeric antibody reactions
There was a low incidence (<2%) of human anti-mouse antibody and human anti-chimeric antibody reactions. However measurements in the studies were at baseline, 4, and 12 weeks post-treatment. New information indicates that these antibodies could develop over several months in up to 12 months likely related to the period of depletion of lymphocytes. It is recommended that data be collected in the post-marketing period over longer intervals to determine the true incidence and duration of such reactions. Of note, human anti-mouse antibody and human anti-chimeric antibody reactions were not associated with any significant clinical problems.
Second malignancies
Second malignancies were observed in the Zevalin-treated patients. Three had acute myelogenous leukemias, 2 had myelodysplastic syndromes and one individual had a meningioma. The onset of malignancies was 8-34 months following therapy and approximately 4-13 years following the diagnosis of lymphoma. The overall incidence rate of second malignancies was 1.4%. This is within the range of incidence in patients who are heavily pre‑treated with cytotoxic chemotherapy and who have received alkylating agents. It is therefore not a significant concern with the use of Zevalin therapy, although these events should continue to be carefully monitored.
Deaths
There were 69 deaths in patients entered in the Zevalin trials (N=349). Of these deaths, 13 occurred on study and 56 were reported during post-study follow-up. These deaths were due to the following causes:
- 57 were due to progressive disease
- 2 were from neutropenic sepsis following additional chemotherapy
- 5 from myelodysplasia/acute myelogenous leukemia, second malignancies
- 5 due to unrelated or pre-existing illnesses
There were two treatment-related deaths both due to traumatic intracranial hemorrhage at the time of platelet nadirs. One patient was on Coumadin for treatment of a deep vein thrombosis and was taking self-prescribed ibuprofen. It is recommended for patients on Coumadin to be excluded, or be carefully watched during the nadir period. This is adequately addressed in the Product Monograph.
Non-hematologic laboratory toxicity
The effects of 90Y-Zevalin on liver and renal function, and on other laboratory parameters are unremarkable. The most frequently observed abnormalities are elevated alkaline phosphatase (6%) and total bilirubin (5%). None of these grade 3 or grade 4 abnormalities were assessed by the investigator as related to treatment with 90Y-Zevalin.
Conclusion
Compared with the toxicity experienced with chemotherapy, 90Y-Zevalin was associated with a low incidence of side-effects particularly non-hematologic toxicity. The dose limiting toxicities were hematologic. The incidence of nadirs developed over a longer interval when compared to chemotherapy, but the time of recovery was similar. In all cases this was reversible and was associated with a lower rate of severe infections.
3.3.6 Issues Outstanding
Long-term treatment issues
Issues to be addressed in a post-marketing phase:
- More data are needed to evaluate the effect of therapy with Zevalin on time to progression with regards to follicular lymphomas.
- Insufficient data are available to evaluate clinical benefits of Zevalin in patients with transformed lymphomas. Additional data is needed for authorization of the drug in this subgroup of patients.
- Human anti-mouse antibody and human anti-chimeric antibody reactions should be monitored over longer periods of time following treatment, in view of documentation of antibody development over several months.
- Ongoing monitoring of patients is needed to document the incidence of second malignancies.
- Insufficient data are available to assess the effect of radiolabelled therapy on gonadal and hormonal function. Such information will need to be collected in the future.
Drug interactions
Caution should be exercised with the use of anticoagulants and other drugs affecting platelet function such as non-steroidal anti-inflammatory drugs (NSAIDs).
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Benefit
This priority New Drug Submission contains data in support of a novel compound, Zevalin (ibritumomab tiuxetan), for the treatment of patients with relapsed or refractory low-grade or follicular, CD20+ B-cell non-Hodgkin's lymphoma, including patients with rituximab-refractory follicular non-Hodgkin's lymphoma. The target population consists of patients with a diagnosis of low-grade or follicular lymphomas that are relapsed or refractory to prior chemotherapy or rituximab. This patient population is elderly with a median age of 60-65 years, an age group where second- and third-line chemotherapies are comparatively poorly tolerated with a negative impact on quality of life. This population is usually heavily pre-treated with advanced and often bulky disease. With sequential progressions, these patients respond poorly to further chemotherapy. As such, effective and better tolerated therapy is needed for these patients.
Treatment with a single dose of [90Y] Zevalin has demonstrated clinical benefit with significant responses (up to 80% of patients), and time to progression for responding patients exceeding 12 months. Similar response rates and durations of remission are observed when Zevalin is given to patients who are refractory to rituximab; or when given at a lower dose to patients with mild thrombocytopenia. The overall response rate and duration of response with 90Y-Zevalin corresponds favourably to other second- and third-line chemotherapy regimens, including rituximab (which has response rates of approximately 50% and time to progression of 9 months) and fludarabine phosphate (which has response rates of 32-62%).
Given that 90Y-Zevalin directs radiotherapy specifically to tumour sites, its toxicity to normal tissues is reduced with low incidence of side-effects, in particular non-hematologic toxicity. It is therefore an appropriate therapy in this clinical setting and age group. An additional benefit is that the 90Y-Zevalin regimen is completed following two out-patient visits, one week apart, and requires no special gowning or isolation measures. Consequently, the 90Y-Zevalin therapy has a favourable rate of acceptability by patients.
In addition, the hematological toxicity is comparable to that of standard chemotherapy, although showing a different time course. The rate of serious infection, including febrile neutropenia, is substantially lower than expected during severe neutropenia episodes. This is likely due to the lower incidence of gastrointestinal toxicities.
Although the major toxicity of 90Y-Zevalin is hematological, patients with compromised marrow function or heavy marrow infiltration can still be treated effectively with the 90Y-Zevalin regimen, given at a reduced dose, as demonstrated in the study with mild thrombocytopenia.
Risk
Data accumulated from the five clinical trials provided adequate safety measures from biodistribution imaging studies and clearly characterized toxicity risks associated with the 90Y-Zevalin therapy. Appropriate and safe dose adjustment in patients with mild thrombocytopenia was demonstrated in clinical studies and is outlined in the Product Monograph. Patients at higher risk of hematologic toxicity (e.g., platelet count less than 100,000/mm3) were excluded from clinical studies; conditions associated with increased hematologic toxicity are adequately addressed in the Product Monograph.
The majority of non-hematologic adverse events consisted of Grade 1 or 2 constitutional symptoms, such as asthenia, nausea, fever, and chills. The incidence of these events was similar to those associated with rituximab therapy. Of note, non-hematological toxicity did not include alopecia, mucositis and vomiting, events commonly associated with combination chemotherapies.
The main risks associated with 90Y-Zevalin therapy are primarily hematological in nature, with a high incidence of grade 3 and 4 neutropenia and thrombocytopenia. The timing of nadirs has been well characterized, developing in up to 60 days after therapy. Patients' characteristics that correlate with higher risks of hematological toxicities have also been identified. In most cases, hematological toxicity is reversible with an average recovery of 2-3 weeks after their incidence. However, patients should continue to be monitored weekly after treatment until recovery.
The possibility that 90Y-Zevalin, like other radiopharmaceuticals, induces stem cell toxicity has been noted. Stem cell depletion, if it occurs, appears to be reversible and does not significantly compromise subsequent chemotherapies or stem cell harvest as required for myeloablative therapy with stem cell support. Leukemias and myelodysplasias are known complications of anti-lymphoma treatment with alkylating agents, and have been reported in some patients who were treated with 90Y-Zevalin. The available data suggest that the incidence is not higher than that observed with other anti-cancer agents.
The patients at risk of excessive myelo-toxicity have been clearly identified and it is recommended to either exclude them from treatment, or to reduce the dose to a tolerable level as demonstrated with the use of 0.3 mCi/kg in mild thrombocytopenic patients. In addition, appropriate criteria have been established by the proposed contraindication of patients who have inadequate marrow reserves (including patients with platelet counts <100,000/mm3), patients who have received prior autologous bone marrow transplantation or stem cell support, and patients with prior external beam irradiation involving >25% of active marrow. 90Y-Zevalin is also contraindicated in patients with >25% marrow involvement, since this may result in the targeted delivery of excessive radiation doses to red marrow.
A low incidence (<2%) of human anti-murine antibody formation was observed with no significant clinical consequences. 90Y also does not emit penetrating gamma radiation; therefore patient isolation and shielding are unnecessary. In addition, treatment can be administered on an out-patient basis with a shorter treatment duration in comparison to both immunotherapy and traditional chemotherapy. This represents a considerable convenience and quality of life benefit for the patient.
Evaluation of the overall clinical benefit of Zevalin in the population studied, is based on the knowledge that these patients have a disease which is ultimately incurable, requiring access to effective therapy for symptom management. Currently, no treatment has been shown to prolong survival. In this context, a clinically meaningful outcome is in the form of a significant reduction in tumour burden (as evidenced by objective responses) and resolution of disease-related symptoms sustained for a period of time during which further treatment is not required. In addition, the risk of bleeding from interaction with Coumadin and non-steroidal anti-inflammatory drugs (NSAIDs) is well-documented and proper preventive measures have been well-outlined.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Zevalin is favourable in the treatment of patients with relapsed or refractory low-grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma including patients with rituximab-refractory follicular non-Hodgkin's lymphoma. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005, and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Zevalin®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2001-09-25 |
| Request for priority status | |
| Filed: | 2001-11-13 |
| Approval issued: | 2001-12-17 |
| Submission filed: | 2002-02-15 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2002-04-05 |
| Response filed: | 2002-05-06 |
| Screening Acceptance Letter issued: | 2002-05-10 |
| Update Notice issued: | 2002-11-12 |
| Response filed: | 2003-02-07 |
| Review 1 | |
| Radiation Dosimetry Evaluation complete: | 2005-04-06 |
| Quality Evaluation complete: | 2005-05-03 |
| Clinical Evaluation complete: | 2005-04-06 |
| Labelling Review complete: | 2005-05-03 |
| NOC issued by Director General: | 2005-05-10 |