Summary Basis of Decision (SBD) for ^PrADCETRIS

Date SBD Issued: 2013/04/03

Contact: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

Brentuximab vedotin
50 mg, lyophilized powder for solution, intravenous
Drug Identification Number (DIN): 02401347
Seattle Genetics, Inc.
New Drug Submission Control Number: 154851

For information related to the original authorization of the product, please see the Summary Basis of Decision (SBD) below.

Phase II SBDs (that is, SBDs for eligible drugs authorized after September 1, 2012) will be accompanied by a Post-Authorization Activity Table (PAAT) that will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. When the PAAT for Adcetris becomes available, a link will be provided here.

Summary Basis of Decision for Adcetris

On February 1, 2013, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Seattle Genetics, Inc. for the drug product Adcetris. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Adcetris is favourable for:

• The treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates;
• The treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen.

The indications were authorized based on promising response rates demonstrated in single-arm trials. No data demonstrate increased survival with Adcetris.

1. What was approved?
2. Why was Adcetris approved?
3. What steps led to the approval of Adcetris?
4. What follow-up measures will the company take?
5. What post-authorization activity has taken place for Adcetris?
6. What other information is available about drugs?
7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Adcetris, an antineoplastic agent, was authorized for:

• The treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates;
• The treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen.

The indications were authorized based on promising response rates demonstrated in single-arm trials. None of the data demonstrated increased survival with Adcetris.

Adcetris should only be administered by a qualified healthcare professional experienced in the use of antineoplastic therapy. The safety and efficacy of Adcetris have not been established in the geriatric or pediatric population.

Adcetris is contraindicated for patients who are hypersensitive to any ingredient in the formulation or component of the container. Concomitant use of Adcetris and bleomycin is contraindicated due to pulmonary toxicity. Adcetris is contraindicated for patients who have or have had progressive multifocal leukoencephalopathy. Adcetris was approved for use under the conditions stated in the Adcetris Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Adcetris (50 mg, brentuximab vedotin) is presented as a lyophilized powder for reconstitution with 10.5 mL of sterile Water for Injection, USP (United States Pharmacopeia). In addition to the medicinal ingredient, the powder contains sodium citrate dihydrate, citric acid monohydrate, trehalose dihydrate, and polysorbate 80.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Adcetris approved?

Health Canada considers that the benefit/risk profile of Adcetris is favourable for:

• The treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates;
• The treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen.

Both indications were authorized based on promising response rates demonstrated in single-arm trials. Adcetris was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further studies to confirm the clinical benefit.

Autologous stem cell transplant plays an integral role in the treatment of patients with HL who do not respond to, or relapse after, front-line therapy; however, few treatment options are available for relapsed or refractory HL in patients who have undergone an ASCT, or are not candidates for an ASCT. Studies have indicated that the overall survival (OS) of HL patients that have failed ASCT is short, especially considering the relative youth of this target population. Furthermore, response rates for this particular target population have historically been low in patients receiving salvage therapies.

Systemic ALCL is a serious, life-threatening disease that could potentially be cured with frontline therapies; however, disease recurs in approximately 40-65% of the patients during the first 1-2 years following diagnosis. Salvage therapies offer limited benefit to these patients. Currently, sALCL patients who have failed frontline therapies represent an unmet medical need.

Hodgkin lymphoma and sALCL cells characteristically express the cell-surface receptor CD30. Adcetris (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting of three components:

1. the chimeric immunoglobulin G1 (IgG₁) monoclonal antibody cAC10, specific for human CD30;
2. monomethyl auristatin E (MMAE), a potent microtubule-disrupting agent; and
3. a protease-cleavable covalent linker that attaches cAC10 to MMAE.

Non-clinical studies have demonstrated the anti-cancer activity of brentuximab vedotin. Data from these studies suggest that this anti-cancer activity is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic cell death. The release of MMAE by CD30-independent mechanisms, as well as contributions to the mechanism of action by other antibody-associated functions have not been excluded.

Adcetris has shown promising efficacy in both HL and sALCL patients. The market authorization with conditions was based on the results of two pivotal studies that evaluated the efficacy and safety of the drug product in these target populations. No data demonstrate increased survival with Adcetris. The safety and efficacy of Adcetris have not been established in the geriatric or pediatric population.

Study SG035-0003 (herein referred to as Study 3) was a single-arm, open-label, multicentre, Phase II study that enrolled 102 relapsed or refractory HL patients that had undergone an ASCT. Patients were treated with up to 16 cycles of Adcetris monotherapy administered every 21 days by intravenous (IV) infusion at a dose of 1.8 mg/kg. The overall objective response rate (ORR) per independent review facility (IRF) was the primary endpoint. Patients receiving Adcetris demonstrated a substantial ORR of 75% and a high rate of complete response (CR) of 32%. Duration of response (DOR) was the key secondary efficacy endpoint. Responders had a median DOR of 6.7 months [95% Confidence Interval (CI): 3.6, 14.8]. These findings, in combination with a safety profile that is considered manageable and typical of microtubule disrupting therapeutics, resulted in a benefit/risk profile that was considered favourable for this indication.

Study SG035-0004 (herein referred to as Study 4) was a single-arm, open-label, multicenter, Phase II study that enrolled 58 patients with relapsed or refractory sALCL. Patients were administered Adcetris at a dose of 1.8 mg/kg every 21 days for up to 16 cycles. The ORR per IRF was the primary endpoint. Duration of response was a key secondary endpoint. Adcetris demonstrated a clinically relevant ORR of 86%, with a high CR rate of 59%. The median DOR was 13.2 months [95% CI: 5.7, NE (not estimatable)]. In view of these promising efficacy results and the manageable safety profile, the overall benefit/risk profile appears to be favourable for sALCL patients who failed frontline therapies.

The most commonly observed treatment-emergent adverse events (TEAEs) in Study 3 were neutropenia, peripheral sensory neuropathy, fatigue, nausea, upper respiratory tract infection, diarrhea, pyrexia, vomiting, and cough.

For Study 4, the most common TEAEs occurring in ≥20% of patients included fatigue, pyrexia, nausea, diarrhea, constipation, rash, and most importantly infections, peripheral neuropathy and hematological toxicity. Peripheral neuropathy was observed in 33/58 patients (57%), and was unresolved in several patients at the end of the treatment or during follow-up period. Thirty-seven patients (64%) experienced neutropenia, and of these patients, 14 had ≥ Grade 3 neutropenia.

Adcetris contains MMAE, a microtubule-disrupting agent. The safety profile described above is consistent with the profiles of other microtubule disrupting agents.

A Black Box Warning describing serious warnings and precautions has been included in the Product Monograph for Adcetris. John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in Adcetris-treated patients. Contributing factors may include prior therapies and underlying disease that may cause immunosuppression. Healthcare professionals should monitor patients on Adcetris for any new sign or symptom that may be suggestive of PML. Further treatment with Adcetris should be withheld immediately at the first sign or symptom suggestive of PML.

As part of the conditions under the NOC/c Guidance, Health Canada has requested that the sponsor confirm the clinical benefit of the product by submitting the results of confirmatory studies as well as additional data. The complete list of commitments can be found below under item 4. What follow-up measures will the company take? These results will be evaluated by Health Canada as part of the post-marketing commitments.

A Risk Management Plan (RMP) for Adcetris was submitted by Seattle Genetics, Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and to describe measures that will be put in place to minimize risks associated with the product. As part of the NOC/c Qualifying Notice, the sponsor has been requested to provide any updates to the Canadian RMP when available.

Overall, the efficacy results observed in the pivotal studies are promising and the benefits of Adcetris therapy are considered to outweigh the risks. Adcetris has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and pharmacovigilance. Appropriate warnings and precautions are described in the Adcetris Product Monograph and address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring for Adcetris will be ongoing. Further evaluation will take place upon the submission of post-marketing safety data as they become available.

This New Drug Submission (NDS) qualifies for authorization under the (NOC/c) Guidance. This NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the  Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3. What steps led to the approval of Adcetris?

On April 5, 2012, the New Drug Submission (NDS) for Adcetris was accepted for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance. Subsequent review led to the issuance of a market authorization under the NOC/c Guidance, in recognition of the promising evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.

Submission Milestones: Adcetris

Submission Milestone	Date
Pre-submission meeting:	2012/02/02
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance:	2012/04/05
Submission filed:	2012/04/11
Screening
Screening Acceptance Letter issued:	2012/05/22
Review
Quality Evaluation complete:	2012/12/07
Clinical Evaluation complete:	2012/12/07
Biostatistics Evaluation complete:	2012/12/07
Labelling Review complete:	2012/12/04
NOC/c Qualifying Notice issued:	2012/12/07
Response filed (Letter of Undertaking):	2012/12/24
Notice of Compliance issued by Director General under the Notice of Compliance with Conditions (NOC/c) Guidance:	2013/02/01

The Canadian regulatory decision was based on a critical assessment of the Canadian data package that included quality, non-clinical, and clinical data. The foreign reviews completed by the United States Food and Drug Administration (FDA) were consulted as an added reference in the assessment of the non-clinical and clinical studies. Relevant information from the foreign reviews completed by the European Union's centralized procedure European Medicine's Agency (EMA) and the United States FDA that was incorporated into the Canadian data package were used as an added reference in the assessment of the quality studies.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4. What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the  Food and Drugs Act and  Regulations.

In addition to the requirements outlined in the  Food and Drugs Act and  Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to undertake the NOC/c commitments listed below.

Confirmatory Studies

A progress report for the confirmatory studies will be submitted annually, within 60 calendar days of the International Birthdate (IBD) for Adcetris (August 19, 2011).

The final reports for the following two confirmatory studies will be submitted to Health Canada as Supplements to the New Drug Submission (SNDS) to support the frontline therapy indications and to remove the conditions under which the Notice of Compliance (NOC) was issued under the (NOC/c) Guidance. It is understood that the indications for either Hodgkin lymphoma (HL) (to be confirmed by Study C250003) or systemic anaplastic large cell lymphoma (sALCL) (to be confirmed by Study SGN35-014) can be withdrawn if the respective confirmatory studies are unsuccessful.

• 1. Study SGN35-014: A randomized, double-blind, Phase III trial of Adcetris and CH-P (cyclophosphamide, hydroxydaunorubicin, and prednisone) versus (vs.) CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) in the frontline treatment of patients with CD30-positive mature T-cell lymphomas.

  Enrollment of approximately 300 patients is expected with a primary endpoint of progression-free survival (PFS) as determined by an independent blinded review facility (IRF). Overall survival (OS) is a key secondary endpoint. The sponsor indicates that the study was not sufficiently powered to detect a statistical significant increase in OS. The acceptability of the study will be assessed during the full clinical review.

  • This study should ensure that the number of sALCL patients enrolled in the study is sufficiently large to allow an adequate assessment of the efficacy and safety profile of Adcetris in this population.
  • The diagnostic evaluation of sALCL should always include anaplastic lymphoma kinase (ALK) protein status. The number of ALK-positive and ALK-negative patients should be balanced between arms.

  The estimated final report submission date is September 2019.

• 2. Study C25003: A randomized, open-label, Phase III trial of Adcetris in combination with AVD (adriamycin, vinblastine, and dacarbazine) vs. ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) as frontline therapy in patients with advanced Hodgkin Lymphoma (HL).

  Enrollment of at least 1,040 patients is expected with a primary endpoint of modified PFS determined by an IRF. Overall survival is a key secondary endpoint.

  The estimated final report submission date is June 2019.

The final reports for the following confirmatory studies will be submitted to Health Canada as a Supplement to the New Drug Submission-Confirmatory (SNDS-C) as a condition for authorization of Adcetris under this NOC/c.

• 3. AETHERA (Study SGN35-005): A randomized, double-blind, placebo-controlled Phase III study of Adcetris and best supportive care (BSC) vs. placebo and BSC in the treatment of patients at high risk of residual Hodgkin lymphoma following autologous stem cell transplant (ASCT).

  The sponsor acknowledges that this study will be considered as supportive evidence for clinical efficacy, but will not be sufficient to remove the conditional status of approval on its own.

  The estimated final report submission date is June 2014.

• 4. Study SGN35-008B: An open-label clinical pharmacology study of Adcetris in patients with CD30-positive hematologic malignancies: cytrochrome P450 (CYP) 3A4 drug-drug interactions, excretion, and special populations.

  The final report for Part B will include the pharmacokinetics of patients with hepatic and renal impairment [dosing every 3 weeks (q3w)].

  The estimated final report submission date is July 2014.

Commitments

• 5. The severity, duration and reversibility of neuropathy are being studied in the ongoing AETHERA study. The final report will be submitted to Health Canada as indicated above in item 3, with an estimated final report submission date in June 2014.
• 6. Submit safety updates for all on-going clinical trials with Adcetris. The sponsor indicates that the Development Safety Update Report (DSUR) (which includes the safety update for all ongoing clinical studies) will be provided annually within 60 calendar days of the IBD for Adcetris (August 19, 2011).
• 7. Submit to Health Canada any other analyses that have been designated as post-marketing commitments to other international authorisation granting agencies as per section 3.4.4 of the Guidance for Industry, (NOC/c).

Post-Market Safety Monitoring

• 8. Periodic Benefit-Risk Evaluation Reports-Confirmatory (PBRER-Cs) will be submitted to the Marketed Health Products Directorate (MHPD) and the Biologics and Genetic Therapies Directorate (BGTD), Health Canada, every 6 months for 2 years and then on an annual basis until such time as the conditions associated with the market authorization are removed. The PBRER-C will include an analysis of the Adverse Drug Reaction as per the Pharmacovigilance Plan and safety updates from all ongoing clinical studies with Adcetris, and as per International Conference on Harmonisation (ICH) Guideline E2C (R2) for format and content.
  
  The first PBRER-C will be submitted in April 2013, with reports to follow on the schedule stated above.
• 9. Updates to the Canadian Risk Management Plan (RMP) will be provided to Health Canada on the same schedule as the PBRER-C schedule in item 8 above. The sponsor states that an updated RMP will be provided only in the event that an update is considered to be required.
• 10. Comply with the notification and reporting of specific issues of concern as outlined in 3.4.4 of the Guidance for Industry, (NOC/c).

5. What post-authorization activity has taken place for Adcetris?

Phase II SBDs (that is, SBDs for eligible drugs authorized after September 1, 2012) will be accompanied by a Post-Authorization Activity Table (PAAT) that will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will be created after a decision has been made about an applicable post-authorization activity, and the table will continue to be updated during the product's lifecycle. At this time, no PAAT is available for Adcetris. When available, a link to the PAAT will be provided here.

6. What other information is available about drugs?

Up to date information on drug products can be found at the following links:

• See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
• See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
• See the Drug Product Database (DPD) for the most recent Adcetris Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
• See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the (NOC/c) Guidance, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
• See the Patent Register for patents associated with medicinal ingredients, if applicable.
• See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the  Food and Drug Regulations, if applicable.

7. What was the scientific rationale for Health Canada's decision?

Clinical Basis for Decision

Clinical Pharmacology

Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) cells characteristically express the cell-surface receptor CD30. Adcetris (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting of three components:

• the chimeric immunoglobulin G1 monoclonal antibody cAC10, specific for human CD30;
• monomethyl auristatin E (MMAE) - a potent microtubule-disrupting agent; and
• a linker that attaches cAC10 to MMAE.

Non-clinical data suggest that Adcetris exerts its anti-cancer activity through the binding of the ADC to CD30-expressing cells, followed by the internalization of the ADC-CD30 complex and the subsequent release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic cell death of the CD30-expressing tumor cell.

Pharmacodynamics

QT Prolongation

The effect of Adcetris on the QTc interval was evaluated in an intensive, open-label, single-arm study (Study SGN35-007) in 46 evaluable patients with CD30-expressing hematologic malignancies. Patients were administered the recommended therapeutic dose (1.8 mg/kg administered as a 30 minute intravenous infusion once every 3 weeks) and were assessed on Days 1-4 of the first and third week of the 3-week treatment cycles. Electrocardiogram (ECG) measurements taken at and around the time of the maximum plasma concentration (C_max) of MMAE and the C_max of the ADC were used to evaluate whether there was an Adcetris effect on the QTc interval.

Administration of Adcetris did not prolong the QTc interval from baseline; however, small increases in QTc interval cannot be excluded because of study limitations. Adcetris was associated with small, but statistically significant, decreases in the QTcF interval (maximum mean decrease from baseline approximately 7 ms. At present, the clinical consequences of QTc shortening of this magnitude are not known. There was no convincing evidence of a treatment-related effect of MMAE on the QRS duration, the PR interval, or heart rate. Because studies to assess the levels of MMAE in subjects with hepatic or renal impairment have not yet been completed, exposure in subjects with compromised elimination is not known.

Limitations of this ECG assessment study include the lack of a placebo control arm to enable correction for background changes in the ECG intervals and lack of a positive control to verify assay sensitivity.

Pharmacokinetics

Drug-Drug Interactions

The results of the drug-drug interaction study, SGN35-008A, indicated that MMAE is unlikely to be an inducer or inhibitor, but is a substrate, of cytochrome P450 (CYP)3A4. There is also the potential that MMAE is a P-glycoprotein (P-gp) substrate; therefore, it is important to note the potential of MMAE to interact with drugs or foods that are inhibitors/inducers of CYP3A enzymes and/or P-gp as these could affect exposures to MMAE. The pharmacokinetics of ADC were not affected by co-administration of any modulators of CYP3A4/P-gp, nor did the ADC affect the pharmacokinetics of midazolam, a CYP3A substrate. This indicates that at the current dosing regimen, CYP3A enzymes are not inhibited by Adcetris or any of its components.

The clinical pharmacology program was considered appropriate and did not identify any major issues that would preclude authorization. At the time of submission, one study (Study SGN35-008B) investigating renal and hepatic impairment was underway but not complete. This study has been designated as a post-marketing commitment.

For further details on the clinical pharmacology of Adcetris, please refer to the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Adcetris was evaluated in two pivotal, single-arm, open-label, multicentre, Phase II studies: Study SG035-0003 (herein referred to as Study 3) and Study SG035-0004 (herein referred to as Study 4). Study 3 enrolled 102 relapsed or refractory HL patients that had undergone an autologous stem cell transplant (ASCT) and Study 4 enrolled 58 patients with relapsed or refractory sALCL. In both studies, patients were treated with Adcetris monotherapy administered every 21 days by intravenous (IV) infusion at a dose of 1.8 mg/kg for up to 16 cycles.

For both studies, the primary endpoint was the overall objective response rate (ORR), defined as the proportion of patients who achieved complete response (CR) or partial response (PR). Response was determined by an independent review facility (IRF) that assessed response using standardized response criteria for malignant lymphoma. These criteria are widely accepted for use in the measurement of response in clinical studies for malignant lymphoma.

Secondary endpoints included duration of response (DOR) per IRF, CR rate per IRF, Progression-Free Survival (PFS) per IRF, and Overall Survival (OS). The DOR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first subsequent documentation of objective tumor progression or to death due to any cause, whichever came first. The CR rate per IRF was defined as the proportion of patients achieving CR according to standardized response criteria. Progression-Free Survival per IRF was defined as the time from start of study treatment to first documentation of objective tumor progression or to death due to any cause, whichever came first. Lastly, OS was defined as the time from start of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was to be censored at the last date the patient was known to be alive. Patients lacking data beyond the day of first dose were to have their survival time censored at 1 day.

The resolution rate of B symptoms was an additional endpoint in both studies, and was defined as the proportion of patients with lymphoma-related B symptoms at baseline who achieved resolution of all B symptoms at any time during the treatment period.

Hodgkin Lymphoma

An independent radiological and clinical data review that applied standardized response criteria determined that 75% [76/102; 95% Confidence Interval (CI): 64.9; 82.6] of patients achieved an objective response while receiving Adcetris monotherapy. Of these 76 patients, 33 [32% (95% CI: 23.4; 42.3)] were assessed as having a CR at one or more time-points. Forty-three patients [42% (95% CI: 32.4; 52.3)] had a best clinical response of PR. The lower bound of the 95% CI around the ORR substantially exceeded the pre-defined limit of 20% and, therefore, the ORR was considered to be both clinically and statistically significant.

The DOR (key secondary endpoint) for HL patients receiving Adcetris was considered to be durable. Overall, responders had a median DOR of 6.7 months (95% CI: 3.6; 14.8). The median duration of response was not reached in CR patients [95% CI: 10.8, NE (not estimatable)] while patients that achieved PR had a median DOR of 3.5 months (95% CI: 2.2; 4.1). The median time to objective response was 5.7 weeks (range: 5.1 - 56 weeks) and the median PFS was 5.6 months (95% CI: 5.0; 9.0). Median OS was estimated to be 27.0 months (95% CI: 23.9, NE); however, in the absence of a comparator arm, it is difficult to put the results of time-to-event endpoints, such as PFS and OS, into context. Therefore, it is imperative that confirmatory studies are adequately designed to properly characterize these key endpoints.

The resolution of B-symptoms was investigated as an additional endpoint. Thirty-five patients had B-symptoms at baseline. Of these, 27 (77%) had complete resolution of B-symptoms at some time after the initiation of treatment.

Systemic Anaplastic Large Cell Lymphoma (sALCL)

Patients treated with Adcetris demonstrated an ORR per IRF of 86% (50/58 patients; 95% CI: 74.6; 93.9). Fifty-nine percent (59%) (34/58 patients; 95% CI: 44.9; 71.4) of patients had a CR and 28% (16/58 patients; 95% CI: 16.7; 40.9) had a PR. The lower bound of the 95% CI for ORR substantially crossed the pre-specified limit of 20%, therefore the ORR was considered to be statistically and clinically meaningful.

The median DOR per IRF was 13.2 months (95% CI: 5.7, NE). The responses were durable for CR responders (not reached, 95% CI 13.0, NE), but not for PR responders (2.0 months, 95% CI 0.1, 21+); however, these results should be interpreted with caution as patients who achieved a CR may have pre-treatment characteristics that favour a longer duration of response compared to PR responders.

The ORR per IRF was consistent with that per investigator and among most of the subgroups. The median time to objective response was 5.9 weeks (range 4.3-14 weeks). The estimated median PFS per IRF was 14.3 months (95% CI: 6.9, NE) and the median OS was not reached. At the time of the study closure, 55% of patients had progressed or died, and 33% of the patients had died. In the absence of a comparator arm, these results are difficult to interpret. In addition, 14 out of 17 patients (82%) had resolution of their B symptoms, but this result should be interpreted with caution as only a small proportion of patients had B symptoms at baseline (17 patients; 29.3%). Confirmatory studies are warranted to assess the true clinical benefit of Adcetris.

Supportive Studies

Data from one single-arm, open-label, multi-centre, first-in-human, Phase I dose-escalation study (Study SG035-0001 - herein referred to as Study 1) provided support for the efficacy of Adcetris in patients with CD30-positive haematological malignancies. The study enrolled 45 patients. The primary objective of the study was to characterize the safety of Adcetris monotherapy and to determine the maximum-tolerated dose (MTD) of Adcetris when administered once every three weeks. Secondary objectives were to characterize the efficacy and pharmacokinetics for Adcetris and for the cytotoxic portion of Adcetris, MMAE.

For patients receiving a dose of 1.8 mg/kg (n = 12), the ORR was 50%. This level of response was supportive of the high rates of response (75%) observed in the pivotal studies.

Overall Analysis of Efficacy

In conclusion, both pivotal studies met their primary endpoint by achieving a high ORR in the indicated populations. Furthermore, a Phase I study (Study 1) in which a limited number (12 of 45 subjects who took part in the study) of patients with CD30 positive haematological malignancies received Adcetris monotherapy at a dose of 1.8 mg/kg every 3 weeks also detected a high rate of response. Duration of response was a key secondary efficacy endpoint in both pivotal studies, and responses were considered to be durable in both the HL and sALCL populations. Other measures of efficacy common to both pivotal trials included PFS and OS; however, in the absence of a comparator arm, time-to-event endpoints [that is (i.e.) PFS, OS,] are difficult to interpret and no definite conclusions on these efficacy results can be drawn.

Based on the primary endpoint (ORR) results, in combination with the demonstration of durability of response, Adcetris therapy is considered likely to be efficacious in the population in which it was tested. Confirmatory studies are warranted to assess the true clinical benefit of Adcetris and are required in order to fulfill commitments agreed upon with the sponsor.

The original indications proposed with the New Drug Submission were as follows:

• Treatment of patients with HL after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.
• Treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

Following review of the submission, Health Canada revised the indication to include the following statement:

• The indications were approved based on promising response rates demonstrated in single-arm trials. No data demonstrate increased survival with Adcetris.

For more information, refer to the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Adcetris was evaluated in the pivotal and supportive studies described in the Clinical Efficacy section.

Hodgkin Lymphoma

Of the 102 patients in the safety evaluable set, 100 (98%) experienced at least one treatment-emergent adverse event (TEAE) that was considered related to study drug by the investigator. A total of 41 patients (40%) experienced a Grade 3 TEAE; 14 patients (14%) had a Grade 4 TEAE; and 1 patient had a Grade 5 (fatal) TEAE. There were 94 patients (92%) who had at least one adverse event (AE) considered related to study drug by the investigator.

The key TEAEs that occurred in ≥20% of patients were neutropenia (54%), peripheral sensory neuropathy (52%), fatigue (46%), nausea (42%), upper respiratory tract infection (47%), diarrhea (36%), pyrexia (29%), thrombocytopenia (28%), vomiting (22%), and cough (21%). Infusion reactions were observed in 12% of patients, but were generally mild (all ≤ Grade 2). One case of Stevens-Johnson syndrome (Grade 3) was reported. The patient developed the AE approximately 2 weeks after the first dose of Adcetris. The AE resolved within 1 month; however, the patient discontinued treatment due to the AE. The risk of Stevens-Johnson syndrome is included as a warning in the Product Monograph for Adcetris. Monomethyl auristatin E (MMAE), one of the components of Adcetris, is a microtubule disrupting agent, and this AE profile is consistent with the profiles of other microtubule disrupting agents.

Twenty patients (20%) had an AE that led to treatment discontinuation. Serious adverse events (SAEs) were experienced by 25 patients (25%); 14 of these patients (14%) had an SAE that was considered related to study drug by the investigator. The most commonly experienced SAEs by System Organ Class were 'Infections and Infestations' (9%); 'Respiratory, Thoracic, and Mediastinal Disorders' (8%); 'Gastrointestinal Disorders' (5%); and 'Nervous System Disorders' (4%). Notably, no cases of neutropenia were considered to be SAEs, and a total of 3 cases of peripheral neuropathy were considered serious.

No deaths occurred within 30 days of the last dose of Adcetris. The single death reported during the study was related to disease progression. On Study Day 13 this patient had an SAE (endobronchial tumor as a result of recurrent HL). The patient died >30 days after receiving the last dose of Adcetris; however, as the initial event occurred during the study, the death is captured in the database as an AE with an outcome of death.

Systemic Anaplastic Large Cell Lymphoma

In Study 4, the safety population included all 58 patients enrolled in the trial. All patients experienced at least 1 TEAE. The most common TEAEs occurring in ≥20% included fatigue (38%), pyrexia (34%), nausea (40%), diarrhea (29%), constipation (22%), rash (24%), and most importantly infections, peripheral neuropathy, and hematological toxicity. Peripheral neuropathy was observed in 33/58 patients (57%), and was unresolved in several patients at the end of the treatment or during follow-up period. Thirty-seven patients (64%) experienced neutropenia and of these, 14 patients had ≥ Grade 3 neutropenia. One incidence of Tumour Lysis Syndrome (Grade 3) was also observed. Infusion reactions occurred in five patients (9%; all of ≤ Grade 2 in severity).

Sixteen patients (28%) discontinued treatment due to AEs. The most common AE leading to treatment discontinuation was peripheral sensory neuropathy (6/16 patients; 28%). Thirty-six patients (62%) experienced ≥ Grade 3 AEs and 25 patients (43%) had SAEs. The System Organ Classes with the greatest incidences of SAEs were 'Nervous System Disorders' (7 patients - 12%) and 'Infections' (7 patients - 12 %).

A total of six deaths occurred within 30 days of the last dose of Adcetris. Four deaths were due to disease progression (such as recurrent ALCL in 3 patients and respiratory failure in 1 patient), one death was due to myocardial infarction and acute renal failure (the patient had pre-existing conditions), and one death was due to sudden death (unknown cause, but the patient had a pre-existing disease-related tracheal disorder).

Supportive Studies

The safety profile observed in Study 1 was relatively consistent with the profile observed in the pivotal trials in terms of incidence and type of events experienced.

Study SG035-0002 (herein referred to as Study 2) was a single-arm, open-label, multicentre, Phase I dose-escalation in patients with relapsed/refractory CD30-positive hematologic malignancies. Study 2 included 44 patients in the safety population, most of whom had HL (86%) and only 5 of whom had sALCL (11%). The results of this study determined that the maximum tolerated dose was 1.2 mg/kg. Due to the single-arm nature of this study and differences in study design and protocol, as well as patient populations, a direct comparison of the safety results with the pivotal studies was not feasible; however, the safety profile appears to be fairly consistent with that of both pivotal trials.

QT shortening was observed in CD30-positive patients treated with Adcetris in a clinical pharmacology study. The clinical significance of QT shortening is unknown.

Post-Marketing Experience

Three cases of progressive multifocal leukoencephalopathy (PML) (2 confirmed, 1 suspected) have been reported since the authorization of Adcetris in the United States. One of these cases occurred in a patient enrolled in Study SG35-010 while the other two occurred in subjects that received commercial Adcetris (1 sALCL patient and 1 HL patient). One of these patients died. The other two were in hospice care at the time of the submission; however, both patients' neurological states were worsening. The occurrence of PML in these patients prompted the United States Food and Drug Administration (FDA) to add a Black Box Warning to the United States Prescribing Information (USPI).

Progressive multifocal leukoencephalopathy is the result of an infection of the brain with John Cunningham (JC) virus that is fatal in approximately 30-50% of cases. Those that survive are often left with severe neurological disabilities. John Cunningham virus is carried by most healthy individuals; however, in those that have lowered immune defenses it is able to proliferate in the white matter of the brain. Patients with HL that have had multiple rounds of multi-modal chemotherapies, radiation, and ASCTs are already at risk for the development of this disease. Based on the single-arm pivotal studies submitted, Adcetris also has a suppressive effect on the immune system (lowered neutrophil counts, lymphopenia); therefore, at this time, it would be prudent to assume that Adcetris treatment may increase the risk of PML in HL patients.

One case of Tumour Lysis Syndrome (TLS) was reported in a patient receiving commercial Adcetris. The incident occurred in a patient diagnosed with diffuse large B-cell lymphoma. The event resolved. This was the second case of TLS observed in patients receiving Adcetris and the first spontaneous report.

One case of Steven-Johnson syndrome was reported in a 28-year old female with HL. This is the second case and the first spontaneous report. The first case was reported in Study 3. The patient has recovered.

Appropriate warnings and precautions are in place in the approved Adcetris Product Monograph to address the identified safety concerns. A Black Box Warning describing serious warnings and precautions for PML has been included in the Product Monograph for Adcetris. John Cunningham (JC) virus infection resulting in PML and death can occur in Adcetris-treated patients. Contributing factors may include prior therapies and underlying disease that may cause immunosuppression. Healthcare professionals should monitor patients on Adcetris for any new sign or symptom that may be suggestive of PML. Further treatment with Adcetris should be withheld immediately at the first sign or symptom suggestive of PML.

Overall Analysis of Safety

In summary, the safety database for Adcetris included data from 6 completed clinical studies. These included 357 patients, with CD30-positive hematological malignancies that received at least one dose of Adcetris. One hundred and sixty (160) of these were enrolled in the Phase II, pivotal studies (102 in Study 3; 58 in Study 4). Both Phase II studies were carried out using the authorized dose and schedule, which is 1.8 mg/kg every 21 days for up to 16 cycles. An additional 6 Phase I - III studies were ongoing at the time of authorization. The number of patients exposed and the extent of exposure in the current clinical safety database are considered adequate to characterize the safety profile.

For more information, refer to the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.

Non-Clinical Basis for Decision

The non-clinical pharmacology program of Adcetris evaluated safety, pharmacokinetics, toxicology, and the ability of brentuximab vedotin (the medicinal ingredient in Adcetris) to kill CD30-positive cells in vitro and in vivo as well as the ability to inhibit tumour progression in rodent models of experimental cancer.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Adcetris Product Monograph. No major objections were identified, although a few concerns were noted that require further analyses. In an embryo-fetal development study conducted in rats, the administration of brentuximab vedotin at 3 and 10 mg/kg resulted in embryo-fetal lethality characterized by decreased fetal viability with increased early resorptions and post-implantation loss. At 3 mg/kg, embryo-fetal toxicity occurred in rats at exposures [area under the curve (AUC)] approximately equal to those in humans at 1.8 mg/kg. The exposure (AUC) in rats at the no observed adverse effect level (NOAEL) (1 mg/kg) was less than 0.3-fold the human AUC; thus there is no safety margin for embryo-fetal development. These effects on embryo-fetal development are consistent with the pharmacologic disruption of microtubules caused by monomethyl auristatin E (MMAE). Treatment with brentuximab vedotin poses a substantial risk of embryo-fetal toxicity. To better communicate this health-risk signal, warnings and precautions have been included in the Product Monograph concerning pregnancy.

As agreed upon in the Letter of Undertaking, in addition to the commitments outlined in the Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), the sponsor will address these concerns as follows:

• A final report for the MMAE quantitative whole body radiography study will be provided.
• The potential adverse effect of Adcetris on functions of pituitary gland, adrenal gland, pancreas, thyroid, and male reproductive systems will be investigated by performing further analyses of data from existing non-clinical studies and from an ongoing clinical study. Additional analyses of the existing non-clinical data and a summary of the analyses conducted will be available for a final report submission in July 2013. The AETHERA (SGN35-005) study, as a placebo-controlled study, is the most appropriate clinical study to explore adverse event signals for the listed endocrine and reproductive systems. This estimated final report submission date is June 2014.
• The impact of anti-therapeutic antibody (ATA) on brentuximab vedotin pharmacokinetics and safety is currently being evaluated in the three ongoing confirmatory studies (SGN35-014, C25003, and AETHERA SGN35-005) and will be discussed in the final reports for these submissions (estimated dates are found under Confirmatory Studies).
• The mechanism underlying the time-dependent inhibition of cytochrome P450 (CYP)3A by MMAE will be further investigated and summarized in a report to be submitted in December 2013.
• The reported inhibition of CYP enzymes by MMAE in primary hepatocyte cultures for its underlying mechanism and its relevance in humans will be further investigated and summarized in a report to be submitted in December 2013.

In view of the intended use of Adcetris, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product for the requested indication.

For more information, refer to the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.

Quality Basis for Decision

Characterization of the Drug Substance

The active ingredient, brentuximab vedotin, is a CD30-directed antibody-drug conjugate (ADC) consisting of three components:

• cAC10 - the chimeric IgG₁ antibody, specific for the human cell-surface receptor CD30;
• Monomethyl auristatin E (MMAE) - a potent microtubule-disrupting agent, and
• Linker - a protease cleavable linker that covalently attaches MMAE to cAC10.

Detailed characterization studies were performed to provide assurance that the components of brentuximab vedotin consistently exhibit the desired characteristic structure and biological activity.

Comparability of brentuximab vedotin lots produced by different processes throughout development was demonstrated through analytical characterization using release tests and additional biochemical characterization tests.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be adequately controlled and the established limits were considered to be acceptable.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Drug Substance

The cAC10 and SGD-1006 intermediates are manufactured and released as stable intermediates.

• cAC10 Intermediate - The cAC10 Intermediate is produced in a recombinant Chinese Hamster Ovary (CHO) cell line. The process consists of cell culture, harvest, recovery, and purification stages including viral inactivation/removal steps. Viral validation studies were also found to be acceptable.
• SGD-1006 Intermediate - The SGD-1006 intermediate is the drug-linker component of the ADC brentuximab vedotin bulk drug substance (BDS). The process for manufacture of SGD-1006 consists of a convergent, solution phase, fragment-based peptide synthesis.
• Bulk drug substance (BDS) - The BDS manufacturing process consists of the following steps: cAC10 thawing, pooling and filtration steps followed by a partial reduction reaction, a conjugation reaction [conjugation of cAC10 intermediate to the SGD-1006 intermediate (enzyme-cleavable linker + MMAE)], a quenching reaction, a tangential flow filtration, a formulation, a filtration, and bottling step.

Process validation and batch analysis data demonstrate that the manufacturing process for cAC10, SGD-1006, and the bulk drug substance operates in a consistent manner, yielding product of acceptable quality.

Drug Product

Adcetris is supplied as a single-use vial containing 55 mg of brentuximab vedotin as a sterile, white to off-white lyophilized, preservative-free cake or powder. Prior to administration, the contents of the Adcetris vial are reconstituted with 10.5 mL of Sterile Water for Injection, USP (United States Pharmacopeia) resulting in a clear to slightly opalescent, colourless solution containing 5 mg/mL brentuximab vedotin. In addition, each vial of product contains the following excipients: sodium citrate dihydrate, citric acid monohydrate, trehalose dihydrate and polysorbate 80.

The 50-mg presentation is packaged in a 30 cm³, clear Type I glass vial and sealed with a 20 mm gray butyl lyophilization stopper and an aluminum, push-off seal. Each vial contains a 10% overfill relative to the nominal content.

The drug product manufacturing process consists of the pooling and mixing of the contents of the drug substance followed by sterile filtration, aseptic filling into sterile glass vials, lyophilisation, stoppering, and sealing with aluminum seals.

The validation and batch analysis data demonstrate that drug product manufactured at the commercial scale consistently meets the established release specifications.

There have been no changes to the Adcetris formulation throughout the development history. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the  Food and Drug Regulations. The compatibility of the brentuximab vedotin with the excipients and the container closure system was demonstrated by the stability data presented on the proposed commercial formulation.

Control of the Drug Substance and Drug Product

The drug substance and drug product specifications along with the analytical methods used for the evaluation of the identity, composition, potency and purity of brentuximab vedotin are considered acceptable.

Results from process validation studies indicate that the methods used during processing adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Batch analysis results for cAC10, SGD-1006, the bulk drug substance and the drug product were reviewed and all results comply with specifications demonstrating consistent quality of the batches produced.

In addition, through Health Canada's lot release testing and evaluation program, three consecutively manufactured final product lots were tested for potency and purity, evaluated, and found to meet the specifications of the drug product, thus supporting that data provided by the sponsor and demonstrating consistency in manufacturing.

Stability of the Drug Substance and Drug Product

Based on the real-time and long-term stability data submitted, the proposed shelf-lives for cAC10, SGD-1006, the bulk drug substance, and the drug product are supported and considered to be satisfactory. The proposed 36-month shelf-life at 2 to 8°C for Adcetris is considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production of the drug substance and the drug product are considered suitable for the activities and products manufactured.

An OSE for the cAC10 Intermediate manufacturing site was not warranted as the facility had been previously evaluated for another product and assigned a "C" (compliant) rating. In addition, considering that limited steps are performed at the bulk drug substance manufacturing site and at the drug product manufacturing site, no OSEs were performed for these facilities either.

All sites involved in the production of Adcetris are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The brentuximab vedotin manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom of adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.

With the exception of the cAC10 production cell line, no raw materials of animal or human origin are used directly in the manufacturing of Adcetris. However, some of the raw materials and processing components contain animal-derived product secondary or tertiary to their manufacture. The information provided on these materials has been reviewed and poses no apparent risk of transmission of transmissible spongiform encephalopathy (TSE).

The excipients used in the drug product formulation are not from animal or human origin.