Summary Basis of Decision for Truseltiq
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Truseltiq is located below.
Recent Activity for Truseltiq
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.
Summary Basis of Decision (SBD) for Truseltiq
Date SBD issued: 2021-11-30
The following information relates to the new drug submission for Truseltiq.
Infigratinib (supplied as infigratinib phosphate)
Drug Identification Number (DIN):
- DIN 02520621 - 50 mg infigratinib per dose (a blister pack of 21 doses of two 25 mg capsules), oral administration
- DIN 02520648 - 75 mg infigratinib per dose (a blister pack of 21 doses of three 25 mg capsules), oral administration
- DIN 02520656 - 100 mg infigratinib per dose (a blister pack of 21 doses of 100 mg capsules), oral administration
- DIN 02520664 - 125 mg infigratinib per dose (a blister pack of 21 doses of 100 mg and 25 mg capsules), oral administration
QED Therapeutics, Inc.
New Drug Submission Control Number: 246904
On September 27, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to QED Therapeutics, Inc. for the drug product Truseltiq. 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-harm-uncertainty profile of Truseltiq is favourable for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.
1 What was approved?
Truseltiq, an antineoplastic agent, was authorized for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.
Prior to initiation of Truseltiq therapy, the presence of an FGFR2 fusion or rearrangement should be established using a validated test.
Clinical effectiveness of Truseltiq is based on the overall response rate and duration of response from a single-arm Phase II trial in patients with specific FGFR2 rearrangements.
No data are available to Health Canada regarding the use of Truseltiq in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.
Of the 351 patients treated with Truseltiq at the recommended dose in clinical studies, 33% were 65 years of age or older and 10% were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and patients younger than 65 years of age.
The use of Truseltiq is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Truseltiq was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Truseltiq (25 mg and 100 mg infigratinib, supplied as infigratinib phosphate) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains black iron oxide, colloidal silicon dioxide, crospovidone, gelatin, hypromellose, lactose monohydrate, magnesium stearate (from vegetable source), microcrystalline cellulose, pharmaceutical grade printing ink, red iron oxide, titanium dioxide, and yellow iron oxide.
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 Truseltiq Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Truseltiq approved?
Health Canada considers that the benefit-harm-uncertainty profile of Truseltiq is favourable for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.
Truseltiq 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 follow-up to confirm the clinical benefit.
Cholangiocarcinomas constitute a heterogenous group of malignancies arising from the epithelial cells of bile ducts. They account for approximately 15% of all primary liver cancers and approximately 3% of gastrointestinal malignancies. The silent presentation of these rare tumors, their highly aggressive nature, and refractoriness to chemotherapy contribute to their poor prognosis. Worldwide, the incidence of cholangiocarcinomas is increasing and approximately 2% of all annual cancer-related deaths are due to these malignancies.
Fusions in the fibroblast growth factor receptor (FGFR) gene have been detected in approximately 13% to 17% of intrahepatic cholangiocarcinoma. These fusions generally lead to ligand-independent constitutive activation of the receptor and downstream MAPK-ERK and JAK-STAT signalling pathways, resulting in uncontrolled cell proliferation, survival, and migration.
Infigratinib, the medicinal ingredient in Truseltiq, is an orally bioavailable, potent, and selective adenosine triphosphate (ATP)-competitive inhibitor of FGFR1, FGFR2, and FGFR3.
The market authorization of Truseltiq was based on the interim efficacy and safety data derived from Cohort 1 of an open-label, single-arm Phase II clinical trial, CBGJ398X2204. Cohort 1 of the trial included 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. Patients received Truseltiq at a dosage of 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles, until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate and duration of response, as determined by a blinded independent central review according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline, version 1.1.
Treatment with Truseltiq resulted in an overall response rate of 23.1% (95% confidence interval [CI]: 15.6% to 32.2%) and a median duration of response of 5.03 months (95% CI: 3.71 to 9.26 months). These findings are considered clinically meaningful, given that the life expectancy is 5 to 6 months for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. However, the promising evidence of efficacy demonstrated by the single-arm CBGJ398X2204 trial needs to be confirmed in a randomized, Phase III confirmatory trial. Further evaluation will take place upon the submission of the confirmatory trial report.
Among the 108 patients of Cohort 1 in the CBGJ398X2204 trial, the most commonly occurring adverse reactions to Truseltiq (at an incidence rate of at least 20%) were nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, and vomiting. The most commonly reported laboratory abnormalities were increased creatinine, and calcium-phosphate homeostasis abnormalities (hypercalcemia, hyperphosphatemia, and hypophosphatemia).
Serious risks associated with the use of Truseltiq include ocular toxicity (in particular, retinal pigment epithelial detachment [RPED]) and hyperphosphatemia, both of which are class-specific adverse effects of FGFR2 inhibitors. Among the 108 patients of Cohort 1 in the CBGJ398X2204 trial, RPED was reported in 17% of patients. Hyperphosphatemia, based on laboratory values of serum phosphate above the upper limit of normal, was reported in 89% of these patients.
The identified serious risks are highlighted in the Adverse Reactions table and Warnings and Precautions section of the Truseltiq Product Monograph. As demonstrated in the pivotal trial, the risks are manageable by dose modification, dose discontinuation, and standard supportive care. These mitigation strategies are outlined in the Truseltiq Product Monograph. In addition, educational material to assist health care professionals with the diagnosis and management of RPED will be available through the manufacturer.
A Risk Management Plan (RMP) for Truseltiq was submitted by QED Therapeutics, 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.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Truseltiq Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Truseltiq was accepted.
Overall, the benefits of Truseltiq therapy seen in the CBGJ398X2204 trial are promising and are considered to outweigh the potential risks for the intended population of previously treated patients with cholangiocarcinoma harbouring an FGFR2 fusion or other rearrangement. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Truseltiq Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, monitoring the safety of the drug will be ongoing. Further evaluation will take place upon the submission of the confirmatory trial report.
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 Truseltiq?
At the pre-submission meeting of October 5, 2020, the sponsor requested Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the New Drug Submission (NDS) for Truseltiq. Upon assessment of the presented information, Health Canada determined that the eligibility criteria were met for the NDS to be filed and reviewed under the NOC/c policy. There was promising evidence of clinical effectiveness that the drug would provide effective treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement, which is a serious and life-threatening disease with a significant unmet medical need.
The review of the NDS led to the decision to issue a market authorization for Truseltiq under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness presented 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.
The NDS for Truseltiq was reviewed under Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership designed to give cancer patients faster access to promising cancer treatments. The submission for Truseltiq was classified as a Project Orbis type A submission, which allows for maximal collaboration among regulatory agencies during the drug review phase. For this submission, Health Canada collaborated with the FDA and Australia’s Therapeutic Goods Administration. The Canadian regulatory decision on the review of Truseltiq was made independently and was based on a critical assessment of the data package submitted to Health Canada.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Truseltiq
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-10-05 |
| Advance consideration under the Notice of Compliance with Conditions (NOC/c) Guidance granted | 2020-11-26 |
| Submission filed | 2020-11-30 |
| Screening | |
| Screening Deficiency Notice issued | 2020-12-18 |
| Response filed | 2021-01-05 |
| Screening Acceptance Letter issued | 2021-01-15 |
| Review | |
| Biopharmaceutics evaluation completed | 2021-04-16 |
| Biostatistics evaluation completed | 2021-07-19 |
| Review of Risk Management Plan completed | 2021-07-24 |
| Clinical/medical evaluation completed | 2021-07-27 |
| Labelling review completed | 2021-07-27 |
| Quality evaluation completed | 2021-07-28 |
| Non-clinical evaluation completed | 2021-07-29 |
| Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued | 2021-07-29 |
| Revised Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued | 2021-07-30 |
| Review of Response to NOC/c-QN: | |
| Response filed (Letter of Undertaking) | 2021-08-25 |
| Labelling review completed | 2021-09-07 |
| Clinical/medical evaluation completed | 2021-09-20 |
| Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance | 2021-09-27 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations and in the Notice of Compliance with Conditions (NOC/c) Guidance.
Notably, the sponsor has agreed to provide the study report from the primary analysis of progression-free survival (as assessed by a blinded independent review) and interim overall survival analysis (performed at the time of final progression-free survival analysis) for the confirmatory study QBGJ398-301, a Phase III, multicentre, open-label, randomized controlled trial comparing Truseltiq (infigratinib) to gemcitabine with cisplatin in patients with advanced/metastatic or inoperable cholangiocarcinoma with FGFR2 gene fusions/translocations.
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 Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- 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 Notice of Compliance with Conditions (NOC/c) Guidance Document, 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?
7.1 Clinical basis for decision
Clinical Pharmacology
Infigratinib, the medicinal ingredient in Truseltiq, is a small-molecule kinase inhibitor of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4).
The pharmacokinetics of infigratinib was studied in healthy subjects and oncology patients, including patients with cholangiocarcinoma. Infigratinib exposure increased more than dose proportionally across the dose range of 5 mg to 150 mg. Steady state was achieved within 15 days. Median time to achieve peak plasma concentration was 6.0 hours (range: 2 to 7 hours). A high variability of pharmacokinetic parameters was observed between study subjects.
In food effect studies in healthy subjects, coadministration of infigratinib with a high-calorie, high-fat meal or a low-calorie, low-fat meal increased exposure by approximately two-fold compared to the exposures achieved under fasted conditions. Therefore, Truseltiq should be taken at least 1 hour before or 2 hours after a meal.
Infigratinib undergoes first-pass hepatic extraction and is metabolized predominantly by cytochrome P450 (CYP) 3A4 (CYP3A4) enzymes. The parent compound has two major active metabolites, BHS697 and CQM157, which contribute about 16% to 33% and 9% to 12% of the overall pharmacologic activity, respectively.
In the first-in-human dose escalation/dose expansion study of infigratinib in oncology patients, the highest daily dose tested was 150 mg. Based on the occurrence of dose-limiting toxicity events, the maximum tolerated dose of infigratinib was declared at 125 mg once daily continuous dosing. The recommended Phase II dosage regimen was 125 mg once daily for 3 weeks followed by 1 week off therapy.
There was no clear exposure-efficacy relationship observed, whereas exposure-safety analyses showed a positive relationship for hyperphosphatemia and eye disorders. Dosage modifications were often needed to manage toxicities in patients receiving the proposed dosage regimen (dose interruption in 64% and dose adjustment in 60% of patients in the CBGJ398X2204 trial [see Clinical Efficacy section]), which resulted in a median relative dose intensity of 78% (approximately 97.5 mg). Therefore, further dose optimization studies would be of benefit in understanding whether the recommended dose is the optimal dose from a clinical pharmacology perspective.
A pharmacokinetic-pharmacodynamic analysis of pooled data did not predict large mean increases from baseline (i.e., over 20 ms) in the heart rate-corrected QT (QTc) interval for the reported maximum plasma concentration (Cmax) value of 295.3 ng/mL (geometric mean Cmax for the 125 mg/day dose on day 15). However, the QT effect of infigratinib at higher exposures, such as those associated with CYP3A inhibition, has not been studied.
Based on data from a hepatic impairment study and population pharmacokinetic analysis, a reduced starting dose of Truseltiq is necessary in patients with mild or moderate hepatic impairment and in patients with mild or moderate renal impairment. No data are available for patients with severe hepatic or severe renal impairment.
A list of reported or potential drug-drug interactions and relevant recommendations to avoid coadministration of Truseltiq with drugs that may increase infigratinib plasma concentrations (strong and moderate CYP3A4 inhibitors) and with drugs that may decrease infigratinib plasma concentrations (strong and moderate CYP3A4 inducers, proton pump inhibitors, histamine-2 [H2] receptor antagonists, and locally acting antacids) have been included in the Truseltiq Product Monograph.
Sufficient data were provided to support bridging between the formulations used in the clinical studies and the commercial formulation of Truseltiq.
For further details, please refer to the Truseltiq Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Truseltiq in patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement was supported by data derived from an open-label, single-arm Phase II clinical trial, CBGJ398X2204. Interim efficacy results were provided from 108 patients (Cohort 1 of this ongoing three-cohort trial).
Ninety-nine percent of patients had metastatic disease at the time of study entry. All patients had received at least one prior line of systemic therapy, 32% had two prior lines of therapy, and 29% had three or more prior lines of therapy. Ninety-nine percent of patients received prior gemcitabine-based therapy and most (88%) had progressed on their prior gemcitabine-based therapy.
Patients were treated with Truseltiq at a dosage of 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles, until disease progression or unacceptable toxicity.
The major efficacy outcome measures were overall response rate and duration of response, as determined by a blinded independent central review according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline, version 1.1. The treatment with Truseltiq resulted in an overall response rate of 23.1% (95% confidence interval [CI]: 15.6% to 32.2%) including 1 patient with a confirmed complete response and 24 patients with confirmed partial responses. The median duration of response was 5.03 months (95% CI: 3.71 to 9.26 months). These results are considered clinically meaningful, given the life expectancy of only 5 to 6 months for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. However, the promising evidence of efficacy demonstrated by the single-arm pivotal trial needs to be confirmed in a randomized, Phase III confirmatory trial.
The drug submission also included data from two non-pivotal studies that evaluated the efficacy of Truseltiq in the treatment of advanced refractory glioblastoma multiforme with FGFR gene alterations (study BGJ398X2201) and a variety of solid tumors with FGFR gene alterations (study CBGJ398XUS04). The efficacy findings of those trials, although limited, supported the findings of the pivotal study.
Indication
The New Drug Submission for Truseltiq was filed by the sponsor with the following proposed indication:
- Truseltiq (infigratinib) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.
- Prior to initiation of Truseltiq therapy, FGFR2 fusion or rearrangement should be established using a validated test.
- Truseltiq has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization.
Following review of the submitted data, Health Canada approved the following indication:
- Truseltiq (infigratinib) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.
- Prior to initiation of Truseltiq therapy, the presence of an FGFR2 fusion or rearrangement should be established using a validated test.
- Clinical effectiveness of Truseltiq is based on the overall response rate and duration of response from a single-arm Phase II trial in patients with specific FGFR2 rearrangements.
For more information, refer to the Truseltiq Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety profile of Truseltiq was evaluated in the pivotal trial CBGJ398X2204 (described in the Clinical Efficacy section). In the primary safety analysis set of 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement who received at least one dose of Truseltiq, the median duration of treatment was 5.52 months (range: 0.03 to 28.29 months).
Additionally, safety data were provided from 243 patients with a variety of cancers treated with Truseltiq as a single agent in three other multicentre single-arm trials. The safety profile of Truseltiq observed in the pooled population of 351 patients was consistent with that observed in the 108 patients from the pivotal study. Assessment of a causal relationship between Truseltiq and treatment-emergent reactions was limited due to the single-arm design of the trials. However, the adverse reactions reported in patients treated with Truseltiq were generally expected given the mechanism of action and the toxicity profile of Truseltiq observed in non-clinical studies.
Among the 108 patients with cholangiocarcinoma enrolled in CBGJ398X2204, the most commonly occurring adverse reactions to Truseltiq (at an incidence rate of at least 20%) were nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, and vomiting. The most commonly reported laboratory abnormalities were increased creatinine, and calcium-phosphate homeostasis abnormalities (hypercalcemia, hyperphosphatemia, and hypophosphatemia).
Serious risks associated with the use of Truseltiq include ocular toxicity (particularly retinal pigment epithelial detachment [RPED]) and hyperphosphatemia, both of which are class-specific adverse effects of FGFR2 inhibitors. Among 351 patients who received Truseltiq across clinical trials, RPED occurred in 11% of patients. Among the 108 patients with cholangiocarcinoma enrolled in CBGJ398X2204, RPED was reported in 17% of patients. This event led to dose interruption/reduction of Truseltiq in 3.4% of patients and permanent discontinuation in 0.6% of patients. Hyperphosphatemia, based on laboratory values of serum phosphate above the upper limit of normal, was reported in 82% of 351 patients who received Truseltiq across clinical trials and in 89% of 108 patients who received Truseltiq in the pivotal trial. The median time to onset of hyperphosphatemia was 8 days (range: 1 to 349 days). Phosphate binders were received by 83% of patients who received Truseltiq.
As demonstrated in the pivotal trial, the risks are manageable by dose modification, dose discontinuation, and standard supportive care. These mitigation strategies are clearly outlined in the Truseltiq Product Monograph. To mitigate the risk of severe RPED, a comprehensive ophthalmologic examination, including ocular coherence tomography, is recommended prior to initiation of Truseltiq treatment, at 1 month, at 3 months, and every 3 months thereafter during treatment. Similarly, laboratory monitoring for hyperphosphatemia is recommended throughout treatment with Truseltiq.
For more information, refer to the Truseltiq Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Infigratinib, the medicinal ingredient in Truseltiq, is a small-molecule kinase inhibitor of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4).
In vitro, infigratinib inhibited FGFR1, FGFR2, FGFR3, and FGFR4 with half-maximal inhibitory concentration (IC50) values of 1.1 nM, 1.0 nM, 2.0 nM, and 61 nM, respectively. Infigratinib inhibited the downstream FGFR signalling and decreased cell proliferation in cancer cell lines with activating FGFR gene amplifications, mutations, and fusions. Constitutive FGFR signalling can support the proliferation and survival of malignant cells.
In vivo, infigratinib exhibited antitumor activity in mouse and rat xenograft models of human tumors with activating FGFR2 or FGFR3 alterations, including two patient-derived xenograft models of cholangiocarcinoma that expressed FGFR2-TTC28 or FGFR2-TRA2B fusions.
Both infigratinib and its major human metabolites, BHS697 and CQM157, were shown to bind FGFRs with similar in vitro binding affinities.
Repeat-dose toxicity studies were conducted in rats and dogs. In a 13-week toxicity study in rats, the highest dose tested was 10 mg/kg/day, resulting in an exposure lower than the human exposure at the recommended clinical dose, based on the area under the concentration-time curve (AUC). Observed toxicities included effects on teeth (incisor degeneration with degeneration of enamel, loss of ameloblast layer and fractures), bones (growth plate thickening in femur and sternum), eye (keratopathy and corneal mineralization), kidney (mineralization), nasal cavity (chondrocytes hypertrophy), tongue and hard palate (decreased epithelium thickness). Following a 6-week recovery period, reversibility was observed for most toxicities, except for the tooth degeneration and kidney and ocular mineralization. The no-observed-adverse-effect level (NOAEL) was considered to be 1 mg/kg/day.
In a 13-week repeat-dose toxicity study in dogs, clinical signs at the highest dose used of 10 mg/kg/day (resulting in an exposure lower than the human exposure at the recommended clinical dose, based on the AUC) included liquid feces throughout the dosing period, inappetence, partially digested food, and generalized thinness starting approximately 8 weeks after dosing and continuing through the end of the dosing period. Microscopic changes were seen in the sternum (growth plate thickening), the meibomian glands (acinar atrophy and ducts dilatation), sebaceous glands (acinar atrophy) and skin (hyperkeratosis). The changes were reversible or showed ongoing recovery (sternum and meibomian glands) after a 6-week recovery period. The NOAEL was considered to be 1 mg/kg/day.
In a 2-week repeat-dose mechanistic study investigating tissue mineralization, histopathological examination showed morphological changes in blood vessels, lungs, kidneys, and bones at a dose of 20 mg/kg/day. Vascular changes included degeneration and mineralization in large blood vessels and in vessels of different organs (heart, gastrointestinal tract, kidneys, and lungs). Bone changes were observed at doses higher than 10 mg/kg/day. Reversibility or a tendency to reversibility was seen in all affected organs. Mineralization was not recoverable.
Reproductive and developmental studies for infigratinib were conducted in rats and rabbits. Exposure of pregnant rats and rabbits to infigratinib caused embryo-fetal death (at a dose of 10 mg/kg/day), reduction in body weights, and fetal abnormalities at maternal exposures lower than clinical exposure (1 mg/kg/day). Based on these results, infigratinib is considered a teratogen.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Truseltiq Product Monograph. In view of the intended use of Truseltiq, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
Appropriate warnings and precautionary measures are in place in the Truseltiq Product Monograph to address the identified safety concerns.
For more information, refer to the Truseltiq 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 Truseltiq 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, a shelf life of 24 months is considered acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).
Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies.
The sites involved in production are compliant with good manufacturing practices.
All non-medicinal ingredients (excipients, described earlier) found in the drug product are acceptable for use by the Food and Drug Regulations. The excipient lactose monohydrate is derived from bovine milk obtained from healthy animals under the same conditions as milk collected for human consumption. The gelatin used in the capsule shells is of bovine origin. Satisfactory information has been provided to establish that these excipients do not pose a risk of contamination with transmissible spongiform encephalopathy agents.