Summary Basis of Decision for Istodax

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Istodax is located below.

Recent Activity for Istodax

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Istodax

Updated:  2023-04-25

The following table describes post-authorization activity for Istodax, a product which contains the medicinal ingredient romidepsin. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02414295 - 10 mg/vial, romidepsin, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Health Professional Risk Communication Not applicable Posted 2023-03-20 Health Professional Risk Communication posted (Istodax [romidepsin] – Restricted Access Program), containing new safety information and information about the product withdrawal for health professionals.
SNDS-C # 254316 2021-06-30 Issued NOC under NOC/c Guidance 2023-03-14 Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission filed the results of confirmatory study RM-PTCL-COOP-0031. The study failed to confirm the clinical benefit of romidepsin in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as a first line treatment for peripheral T-cell lymphoma (PTCL). A NON was issued on 2022-07-11. In response, the sponsor noted no additional plan for confirmatory studies, and provided details on the process to withdraw Istodax from the Canadian market. An NOC was issued under the NOC/c Guidance.
PSUR-C # 248339 2021-01-13 Filed 2021-07-06 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2019-11-05 to 2020-11-04. The information was reviewed and found acceptable. No further action was required.
PSUR-C # 235047 2020-01-10 Filed 2020-05-20 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2018-11-05 to 2019-11-04. The information was reviewed and found acceptable. No further action was required.
SNDS # 219735 2018-08-31 Cancellation Letter Received 2019-08-29 Submission filed as a Level I – Supplement to update the PM with data from a published Phase I study conducted in pediatric patients. The information was reviewed but was not considered acceptable, and a NON was issued on 2019-08-02. The sponsor subsequently cancelled the submission.
SNDS # 219411 2018-08-22 Issued NOC under NOC/c Guidance 2019-07-26 Submission filed as a Level I – Supplement to update the PM with data from study NCI-9008. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, Dosage and Administration, and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Consumer Information. An NOC was issued under the NOC/c Guidance.
PSUR-C # 223632 2019-01-11 Filed 2019-05-30 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2017-11-05 to 2018-11-04. The information was reviewed and found acceptable. No further action was required.
PSUR-C # 212787 2018-01-12 Filed
2018-10-09		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2016-11-05 to 2017-11-04. No further action was required.
PSUR-C # 201843 2017-01-11 Filed
2018-03-07		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2015-11-05 to 2016-11-04. No further action was required.
SNDS # 199398 2016-10-20 Issued NOC
2016-12-20		 Submission filed as a Level I - Supplement (labelling only) for updating the PM, package insert and product labels to reflect a change in the fill volume resulting from an addition of overfill (Post- NOC Changes: Level III). As a result of the submission, the Dosage and Administration, and Dosage Forms, Composition and Packaging sections of the PM were updated, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOC was issued.
PSUR-C # 191448 2016-01-19 Filed
2016-08-12		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. The PSUR-C includes the period from 2014/11/05 to 2015/11/03. The information was reviewed and found acceptable.
PSUR-C # 181569 2015-01-26 Filed
2015-12-23		 Submission filed in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance. The PSUR-C includes the period 2013-11-05 to 2014-11-04. The information was reviewed and found to be acceptable.
NC # 181524 2015-01-22 Issued No Objection Letter
2015-05-01		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph (PM) with new safety information about the potential for fatal reactivation of Epstein Barr Virus infection in patients treated with Istodax. Fatal cases of viral reactivation were reported in patients with relapsed or refractory extranodal Natural Killer (NK)/T cell lymphoma (not an approved indication). As a result of the Notifiable Change (NC), changes were made to the Warnings and Precautions, Adverse Reactions, and Part III Consumer Information sections of the PM. The submission was reviewed and a No Objection Letter was issued.
PSUR-C # 172790 2014-03-05 Cleared
2014-12-24		 Submission filed in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance, for the period 2012-11-05 to 2013-11-04. The information was reviewed and found to be acceptable.
NC # 171728 2014-01-28 Issued No Objection Letter
2014-05-30		 Submission filed as a Level II (120 day) Notifiable Change (Safety Change) to update safety results in the Product Monograph from study GPI-06-0002. As a result of the Notifiable Change (NC), changes were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and minor editorial revisions were made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
NC #170929 2014-01-07 Issued No Objection Letter
2014-04-14		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions and Adverse Drug Reactions sections of the Product Monograph. Additional safety information was added regarding the risk of viral infection reactivation and opportunistic infections in patients treated with Istodax, and additional precision was added to the Drug Interactions section and to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
Drug product (DIN 02414295) market notification Not applicable Date of first sale:
2014-02-05		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the  Food and Drug Regulations.
NDS # 152293 2011-12-10 Issued NOC
2018-03-07		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Istodax

Date SBD issued: 2013-11-26

The following information relates to the New Drug Submission for Istodax.

Romidepsin, 10 mg/vial, lyophilized powder for solution, intravenous infusion

Drug Identification Number (DIN):

  • 02414295

Celgene Inc.

New Drug Submission Control Number: 152293

 

On October 16, 2013, Health Canada issued a Notice of Compliance under the https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/notice-compliance-conditions.html">Notice of Compliance with Conditions (NOC/c) Guidance to Celgene Inc. for the Istodax drug product. The product was authorized under the NOC/c Guidance on the basis of the unmet clinical need and results of the romidepsin's clinical effectiveness in patients who have a poor prognosis. 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 Istodax is favourable for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma (PTLC) who are not eligible for transplant and have received at least one prior systemic therapy.

 

1 What was approved?

 

Istodax (romidepsin for injection), an antineoplastic agent, is indicated for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy. Approval is based on response rates demonstrated in a single-arm study. Improvement in overall survival has not been demonstrated with Istodax.

Istodax (romidepsin) is a novel histone deacetylase (HDAC) inhibitor with pleiotropic activities including induction or repression of gene expression, cell cycle arrest, differentiation, cell growth inhibition, induction of apoptosis, morphological reversion of transformed cells, and inhibition of angiogenesis.

Istodax is contraindicated for patients who are hypersensitive to romidepsin or to any ingredient in the formulation. Istodax was approved for use under the conditions stated in the Istodax Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Istodax (10 mg/vial, romidepsin) is presented as a lyophilized powder for solution. In addition to the medicinal ingredient, the lyophilized powder for solution contains povidone. The diluent contains 80% propylene glycol, and 20% dehydrated alcohol.

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 Istodax Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Istodax approved?

 

Health Canada considers that the benefit/risk profile of Istodax is favourable for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy. Istodax 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.

Non-Hodgkin's Lymphoma (NHLs) are a heterogeneous group of disease originating in various cell lines within the lymphoid system. NHL is divided into broad categories of aggressive or indolent lymphoma and further classified be cell of origin (B or T cells). According to the Revised European-American Lymphoma / World Health Organization (REAL/WHO) classification system, peripheral T cell lymphomas (PTCLs) belong to the subtype of mature T/natural killer (NK) cell neoplasms. Most PTCL subtypes follow an aggressive clinical course with a poor prognosis and patients with this disease require prompt treatment.

According to the most recent statistics, 32,633 Canadians were diagnosed with NHL between 1997 and 2007, which represents up to 3,300 PTCL patients in Canada during that period.

The peripheral T-cell lymphomas are a heterogeneous group of rare disorders that result from clonal proliferation of mature post-thymic lymphocytes. The peripheral T-cell malignancies usually affect adults and most subtypes are more common in men. The disease often presents with involvement of multiple sites, including lymph nodes, blood, bone marrow, spleen, liver, skin, the sinonasal cavity and other groups. PTCL is a life-threatening disease with poor survival outcome. Five year overall survival estimates range from approximately 7% to 32%.

There are currently no pharmaceutical agents approved for use as first-line therapy for PTCL. In general, first line treatments include chemotherapy and Autologous Stem Cell Transplant (ASCT) is recommended for patients who relapse. No therapies have received market authorization in Canada for patients with recurrent or refractory PTCL.

Istodax has been shown to be efficacious in the treatment of patients with relapsed/refractory PTCL. The approval of the drug product is based on results from a single Phase II study that demonstrates a positive benefit/risk assessment under the proposed conditions of use market. Market authorization via Notice of Compliance with conditions (NOC/c) is recommended given the phase II nature of the data and recognizing the unmet medical need for these patients. As part of the proposed commitments, the Sponsor agrees to submit results of a confirmatory Phase III study [Phase III Confirmatory Study in 1st line PTCL comparing the efficacy of Romidepsin-CHOP versus (vs) CHOP alone].

The safety of Istodax (romidepsin for injection) was evaluated in 131 patients with PTCL in the phase II single-arm clinical study (GPI-06-0002). Patients received a starting dose of 14 mg/m². The mean duration of treatment and number of doses were 3.5 months and 11 doses, respectively, corresponding to approximately 4 cycles. The identified serious treatment-related adverse events include pancytopenia, QT interval prolongation, fatal infections, tumor lysis syndrome and potential fetal harm. All of these are listed in a Serious Warnings and Precautions Box in the Istodax Product Monograph.

The most common adverse events reported were functional gastrointestinal (GI) disorders, hematological disorders, asthenic conditions, infections, pyrexia, anorexia, and dysgeusia. Infections were the most common type of serious adverse events (SAE) reported.

The limitations of a single-arm study in establishing a drug's safety profile have been recognized, but, through rigorous safety revisions to the Product Monograph, Health Canada is satisfied that appropriate risk mitigation measures are in place. A Risk Management Plan (RMP) for Istodax was submitted by Celgene 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 when needed, to describe measures that will be put in place to minimize risks associated with the product.

As part of the marketing authorization for Istodax, Health Canada requested that the sponsor agrees to several commitments. These commitments include: submission of the final study report of the Phase III Multi-Center Randomized Study to Compare Efficacy and Safety of Romidepsin-CHOP vs CHOP in Subjects with Previously Untreated Peripheral T-Cell Lymphoma. This study is anticipated to be completed in 2018 and the clinical study report is expected in 2019. The sponsor will provide post-market safety monitoring studies [for example (e.g.) report(s) of all serious adverse drug reactions that occurred in Canada, annual safety summary reports current with the Guidance Document: Notice of Compliance with Conditions]. In addition, appropriate box warnings and precautions shall be inserted in the approved Istodax Product Monograph to address the safety concerns that have been identified up to the time of authorization. Furthermore, the sponsor will file a Supplemental New Drug Submission when the final study report (NCI-9008 Hepatic Impairment Study) assessing the clinical safety of Istodax in patients with advanced cancer and moderate or severe hepatic impairment, is available.

Istodax has an acceptable safety profile based on the non-clinical data and clinical studies. Appropriate warnings and precautions are in place in the Istodax Product Monograph to address the identified safety concerns. Furthermore, all issues raised in the Notice of Non-Compliance have been sufficiently addressed by the sponsor to Health Canada's satisfaction. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Istodax will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

This New Drug Submission 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 Istodax?

 

A Notice of Non-Compliance (NON) was issued for Istodax during the review of the New Drug Submission in regards to quality, clinical and non-clinical aspects of the submission. Main issues identified by Health Canada were as follows: proposed in-use stability data lacking adequate support, insufficient statistical robustness for efficacy based on the single-arm clinical Phase II study, difficulty interpreting a clear safety profile due to limitations in the Phase II clinical study design, and proposed indication by the sponsor was not fully supported by the data package provided. These identified issues were resolved as follows:

Romidepsin drug product is manufactured as a sterile, non-preserved, lyophilized powder in glass vials. Istodax (romidepsin for injection) is intended for intravenous (IV) infusion only after reconstitution with the supplied diluent. Tert-Butyl alcohol and water for injection serve as processing agents for drug product compounding and are removed during the lyophilization process. Residual tert-butyl alcohol, initially limited to ≤1.2 mg/vial in the release specifications for romidepsin lyophilized powder and considered qualified, has been revised to ≤0.8 mg/vial in the response to NON provided. This tightening is considered acceptable. Romidepsin lyophilized powder and diluent for romidepsin are both packaged in USP Type I glass vials sealed with rubber stoppers and have a proposed shelf life of 60 months when stored between 15°C to 30°C.

One clinical issue raised by Health Canada was in reference to the efficacy results of the pivotal phase II (GPI-06-0002) study being viewed only as informative and exploratory. The study is a phase II single arm study in previously treated peripheral T-cell lymphoma (PTCL) patients which demonstrated preliminary and not clinically compelling results. In response, the sponsor provided updated re-evaluation of the primary efficacy endpoint. The overall response rate following the review of the updated data remained unchanged at 26.2% (34 of 130 patients). This extended follow-up is viewed as clinically informative. The patients who have responded to the therapy did maintain the response for a median of 505 days. This is considered a clinically significant benefit. Additionally, the sponsor provided compelling letters from Canadian physicians supporting the use of romidepsin in the treatment of patients with PTCL. The sponsor has committed to provide the results from a confirmatory Phase III Multi-Center Randomized Study Comparing the Efficacy and Safety of Romidepsin-CHOP (Ro-CHOP) vs CHOP in Subjects with Previously Untreated Peripheral T-Cell Lymphoma. The results will be provided to Health Canada in 2019. In addition, the sponsor will provide data from an open-label pharmacokinetic (PK) study NCI-9008 Hepatic Impairment Study of single-dose romidepsin in patients with advance cancer and moderate or severe hepatic impairment. It is deemed that the above studies will provide further evidence of efficacy and safe use of Istodax in patients with PTCL.

Another clinical issue raised was that the true safety profile of Istodax in the PTCL patient population had not been established considering the open-label design of the pivotal study. The treatment-emergent adverse events (TEAEs) were experienced by 91.6% of patients. Serious TEAEs were experienced by 25.2% of patients. During the study 8.4% of patients discontinued due to treatment-related adverse events and eight patients of 131 (6%) died. Additionally, the cardiotoxic profile of Istodax was considered not to be established. In response, the sponsor performed a comparison of the safety results obtained from PTCL patients treated with chemotherapy reported in the literature to those observed in the pivotal study with Istodax. The sponsor provided an updated safety report for the pivotal study which was found to be consistent with that in the New Drug Submission. Additionally a detailed electrocardiogram (ECG) assessment was performed in order to establish the cardiotoxicity profile of Istodax. The sponsor has confirmed to provide the efficacy and safety results from a confirmatory phase III study in the first line PTCL patients who will receive romidepson-CHOP vs CHOP alone. The safety profile of romidepsin will be further defined by the results of this Phase III study.

Lastly, the benefit/risk assessment of romidepsin did not appear favourable. The data package provided did not support the proposed indication. The pivotal study efficacy results were hypothesis generating, preliminary in nature and exploratory. The efficacy results of single agent romidepsin were neither statistically confirmatory nor clinically compelling in light of the high number of patient discontinuations due to drug-related AEs. In response, the sponsor provided updated study results that demonstrate a reasonable level of efficacy, with evidence that some responses can be quite durable. Patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy do represent an unmet medical need, as pointed out by the expert opinions of Canadian physicians. Thus, Istodax could be considered as a valuable treatment option in a patient population where chemotherapy is the only possible treatment in Canada. The efficacy of Istodax is considered to be moderate and the safety profile of the drug product is considered to be manageable.

Other issues captured in the Notice of Non-Compliance (NON) were limited clinical pharmacokinetic (PK) development and toxicology issues. In order to elevate the PK concerns, the sponsor provided two drug-drug interaction (DDI) studies evaluating the effect of the cytochrome P450 (CYP) isozymes 3A4 inhibitor, ketoconazole, and the CYP3A4 inducer, rifampin, on the pharmacokinetics of romidepsin.

Toxicology issues were identified during review of the submission. The formulation of romidepsin had identified two entities, tert-butyl alcohol (TBA) and propylene glycol, which contribute to the risk associated with romidepsin.

In response, the sponsor provided a detailed evaluation of TBA divided into three different exposure categories. A re-analysis of the cumulative incidence of adverse events greater than 10% in patients who received romidepsin was performed. The limit of TBA was tightened which will potentially reduce the risk of long-term exposure to TBA through Istodax.

Another observation during the toxicology review included insufficient exposure in the species tested for repeat-dose toxicity relative to the proposed human dose. Particularly, that some of the observed toxicities may not be reversible. The toxicities related to teratogenicity and reproductive organs have been accordingly labeled in the Product Monograph.

In summary, the overall benefit/risk ratio of Istodax is favourable to support a Notice of Compliance with conditions (NOC/c) market authorization for use in patients with relapsed/refractory PTCL who are not eligible for transplant and have received at least one prior therapy. In addition, the product monograph provides sufficient detail to inform healthcare professionals and patients about the risks associated with Istodax use. Furthermore, all issues raised in the Notice of Non-Compliance (NON) have been sufficiently addressed by the sponsor to Health Canada's satisfaction.

Subsequent review of the sponsor's response to the NON led to the decision to issue the sponsor market authorization under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed 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: Istodax

Submission Milestone Date
Submission filed: 2011-12-20
Screening 1  
Screening Acceptance Letter issued: 2012-02-10
Review 1  
Quality Evaluation complete: 2012-11-28
Clinical Evaluation complete: 2012-11-30
Biostatistics Evaluation complete: 2012-07-19
Notice of Non-Compliance (NON) issued by Director General: 2012-12-03
Response filed: 2013-03-04
Screening 2  
Screening Acceptance Letter issued: 2013-04-18
Review 2  
Quality Evaluation complete: 2013-08-20
Clinical Evaluation complete: 2013-09-06
Biostatistics Evaluation complete: 2013-08-15
Labelling Review complete: 2013-09-06
Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued: 2013-09-09
Response filed (Letter of Undertaking): 2013-09-12
Notice of Compliance (NOC) issued by Director General under the Notice of Compliance with Conditions (NOC/c) Guidance: 2013-10-16

 

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?

 

In addition to 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 provide the following reports:

  • Final study report of "Phase III Multi-Center Randomized Study to Compare Efficacy and Safety of Romidepsin-CHOP (Ro-CHOP) Versus CHOP in Subjects with Previously Untreated Peripheral T-Cell Lymphoma". This study is anticipated to be completed in 2018 and the clinical study report submitted in 2019.

As part of the marketing authorization for Istodax, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • Report(s) of all serious adverse drug reactions (ADRs) that occurred in Canada and all serious unexpected ADRs that occurred outside of Canada will be forwarded within 15 days to the Marketed Health Products Directorate.
  • Annul safety summary reports will be provided to the Therapeutic Products Directorate in a manner consistent with the current Guidance Document: Notice of Compliance with Conditions (NOC/c).

 

5 What post-authorization activity has taken place for Istodax?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) 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 continue to be updated during the product's lifecycle.

The PAAT for Istodax is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

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

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Istodax (romidepsin) is an agent in a class of anticancer agents known as a histone deacetylase (HDAC) inhibitors. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones and induces cell cycle arrest and apoptosis of some cancer cell lines. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

The clinical pharmacokinetic (PK) program of Istodax consisted of studies in subjects with advanced cancer demonstrating dose-proportional and linear PK parametres. The proposed dosing regimen for romidepsin [14 mg/m² IV over a 4-hour period on days 1, 8 and 15 of a 28-day cycle] was evaluated in two Phase I studies and a Phase II study.

In vitro study demonstrated that at clinically achievable concentrations, the human plasma protein binding rates were 82% to 94% for romidepsin. There were no significant differences in protein binding between human serum and plasma. Romidepsin is primary metabolized by the cytochrome P450 (CYP) 3A4/5 enzymes. About 20 different metabolites are formed, of which 9 were identified as main, M1, M3, M7, M8, M10, M11, M12, VMH-1 and VMH-2. Romidepsin does not inhibit or induce CYP activity; however, romidepsin is a substrate for P-glycoprotein (PgP) and multidrug resistance-associated protein 1 (MRP1).

Drug-drug-interaction (DDI) studies evaluating the concomitant administration of romidepsin with CYP3A4 inducers or inhibitors were provided.

A Phase I study evaluated the effects of multiple doses of the CYP3A4 inhibitor, ketaconazole, on the pharmacokinetics of romidepsin. Minimal PK changes were observed, therefore specific dose changes were not recommended. However, the product monograph appropriately reflects that co-administration of romidepsin with strong CYP3A4 inhibitors may result in increased concentrations of romidepsin.

A Phase I study evaluated the effects of multiples doses of the CYP3A4 inducer, rifampin, on the pharmacokinetics of romidepsin. Romidepsin's area under the curve (AUC) was significantly increased by approximately 80% and the Cmax was increased by approximately 60%. It is proposed that this observation is due to rifampin likely limiting the access of romidepsin to the induced CYP3A4 enzyme, resulting in decreased volume of distribution and decreased clearance of romidepsin following rifampin co administration. Due to the significant changes in PK parametres the Product Monograph has been updated to reflect the results and warn that concomitant administrations with strong CYP3A4 inducers should be avoided.

Romidepsin was associated with a large, concentration-dependent increase in heart rate (mean 1820 beats per minute (bpm) increase from baseline at 6 hour post-dosing) at the recommended dose. The QTc data are confounded by pre-medication with QTc-prolonging anti-emetics. The Product Monograph was extensively modified to reflect the concerns raised during the review and to remain consistent with the recommendations of other histone deacetylase (HDAC) inhibitors with respect to ECG effects.

In addition, the sponsor has confirmed that when available, the following study report will be provided: NCI-9008: A Phase 1 and pharmacokinetic single agent study of romidepsin in patients with lymphomas, Chronic Lymphocytic Leukemia and select solid tumors and varying degrees of liver dysfunction.

For further details, please refer to the Istodax Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The pivotal GPI-06-0002 study was a Phase II multi-centre, single-arm, open-label study, evaluating the activity and tolerability of romidepsin in patients [Number (n) = 131] with histopathologically confirmed progressive or relapsed PTCL following prior systemic therapy. Patients received 14 mg/m² intravenously (IV) of Istodax over 4 hours on Days 1, 8, and 15 of each 28-day cycle.

The pivotal study met its primary efficacy endpoint where 17 of 130 patients (13.1%) achieved complete response/unconfirmed complete response (CR/CRu) (radiographic scans assessed as per the International Workshop Criteria, Cheson 1999) based on the Independent Review Committee (IRC) evaluation at the cut-off date of March 31, 2010. The secondary endpoints evaluated 34 patients of 130 (26.2%) with objective response rate (ORR, CR/CRu+PR) and the median duration of response (DOR) was 353 days.

In the response to the Notice of Non-Compliance the sponsor provided updated IRC re-evaluation of primary efficacy endpoint. The CR+Cru increased from 14.6% to 15.4% (20 of 130 patients). The overall response rate following the IRC review of the updated data remained unchanged at 26.2% (34 of 130 patients). This extended follow-up is viewed as clinically informative. The patients who have responded to the therapy did maintain the response for a median of 505 days. This is considered a clinically significant benefit.

In conclusion, based on a clear unmet medical need for improved therapies for patients with relapsed refractory PTCL who have a poor prognosis, the clinically meaningful data observed from the pivotal Istodax study with supportive data from the NCI cooperative group study, and the favorable safety comparisons to existing treatments used in relapsed refractory PTCL, provides a positive benefit-to-risk ratio exists for Istodax in the treatment of patients with relapsed refractory.

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

Clinical Safety

The studies in support of the Clinical Safety section are the same studies described in support of the Clinical Efficacy section.

The safety profile of Istodax in the PTCL patient population was considered to not be established based on the open-label design of the pivotal study. A detailed electrocardiogram (ECG) assessment was performed in order to establish the cardiotoxicity profile of Istodax. The limitations of a single-arm study in establishing a drug's safety profile are recognized, but, through rigorous safety revisions to the Product Monograph, Health Canada is satisfied that appropriate risk mitigation measures are in place.

There were safety concerns related to a toxicological characterization of romidepsin, as well as an impurity in the drug product and a non-medical ingredient in the drug formulation, but the issues were resolved.

The principal adverse events observed with Istodax in patients with PTCL in the pivotal and supporting studies included gastrointestinal (GI) disturbances (83%), hematologic toxicities (66%), asthenic conditions (60%), infections (53%) and clinical chemistry abnormalities (43%). In the pivotal study, over 90% of patients experienced treatment-emergent adverse events (TEAEs) and approximately 25% of patients developed a serious TEAE. Treatment-related discontinuations were noted in 8.4% of patients. Dose delays were experienced by 45.8% of patients. Over 10% of patients required dose reductions, mostly due to thrombocytopenia and neutropenia. During the study 8 patients of 131 (6%) died. Three deaths were due to disease progression and 5 due to infections (3 sepsis, 2 pneumonia). One death (0.8%) was considered to be drug-related and was due to sepsis (infection).

Drug-induced hematological abnormalities were very common: thrombocytopenia (38%), neutropenia (30%), and anemia (24%). Serious adverse events were reported in 46% of patients, of which 19% were infections including pyrexia, sepsis, and pneumonia.

The Phase II study design of the pivotal study [that is (i.e.) lack of comparator arm] does not allow for a true assessment of the safety profile of Istodax.

The risks associated with Istodax are significant, since a high number of patients experienced drug-related serious adverse events and discontinued therapy due to drug toxicity. Nevertheless, the Product Monograph has been extensively revised to inform healthcare professionals and patients about the risks associated with Istodax use. Furthermore, all issues raised in the Notice of Non-Compliance have been sufficiently addressed by the sponsor to Health Canada's satisfaction.

Appropriate warnings and precautions are in place in the approved Istodax Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Pharmacology

The pharmacodynamic (PD) effect of romidepsin has been attributed to a variety of biological effects including histone deacetylase (HDAC) inhibition, acetylation of histone and non-histone proteins, induction or repression of gene expression, cell cycle arrest, differentiation, cell growth inhibition, apoptotic cell death, morphological reversion of transformed cells, and inhibition of angiogenesis. Despite the aforementioned, the exact mechanism associated with the clinical activity of romidepsin has not been fully characterized.

A standard battery of safety pharmacology and PD studies were conducted to investigate the effects of romidepsin on key functions of the cardiovascular, respiratory, and central nervous systems. The ability of romidepsin to interact with targets other than HDACs has not been elucidated. As such, no formal secondary PD studies have been undertaken. Also, no PD drug interaction studies were conducted.

Pharmacokinetics

Romidepsin is primarily metabolized by CYP3A4. Radiolabelled romidepsin was extensively metabolised in rat, dog and human, where at least 28 different metabolites were produced. The structures of these metabolites were identified, but their activity and toxicity were not evaluated. Romidepsin inhibited CYP3A4, CYP2C19, and CYP2D6 at a 20-fold greater concentration than the clinical dose. The information provided has been reviewed and included in the Product Monograph.

Toxicology

The repeat romidepsin administration in the mouse, rat, and dog was associated with toxic effects to the gastrointestinal, hematologic, hematopoietic, cardiac, and reproductive systems and changes in serum chemistries. There was insufficient exposure in the species tested for multiple dosing relative to the proposed clinical dose. The hallmarks of administration of romidepsin to animals were hematopoietic cell depletion in bone marrow accompanied by regenerative anemia and lymphoid depletion of multiple tissues. The effects on the lymphatic/hematopoietic system were observed at all romidepsin dose levels tested in the rat and dog studies, thus a no-observed-effect-level (NOEL) could not be established.

The target organs of romidepsin toxicity were thymus, spleen, liver, heart, kidney, bone marrow, adrenal, salivary and pituitary glands as well as male (testis) and female (ovary, uterus, vagina) reproductive organs. Some of the observed toxicities may not be reversible. At doses lower than the clinical human equivalent dose, the effect of romidepsin on both male and female reproductive organs was irreversible. Maternal and fetal toxicities were observed at doses much lower than the proposed human dose. The embryo-fetal developmental effects of romidepsin were suggestive of teratogenicity. Cardiac toxicity was observed in all species at clinically relevant doses and included congestion and haemorrhage in the heart, as well as myocardial atrophy/necrosis. Furthermore, heart rate-corrected QT interval (QTc) prolongation was observed in dogs, which correlates with inhibition of the human ether-à-go-go related gene (hERG) channel currents by romidepsin. The QT interval corrected for heart rate changes was conducted using the Fridericia's correction method.

The above pre-clinical observations regarding teratogenic, reproductive organ and cardiac toxicities have been accordingly captured in the Product Monograph.

The romidepsin diluent containing 80% (v/v) propylene glycol was identified to cause adverse responses in the pre-clinical studies. Additionally, impurities of the final drug product were identified to contain tert-butyl alcohol (TBA). The levels of these impurities and propylene glycol in the diluent were found to be acceptable pertaining to the requested indication and drug dose.

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

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Istodax has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 60 months is acceptable when stored between 15°C and 30°C.

All sites involved in the production of this drug product are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

 

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