Summary Basis of Decision for Qinlock

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 Qinlock is located below.

Recent Activity for Qinlock

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Qinlock, a product which contains the medicinal ingredient ripretinib. 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 found in Post-Authorization Activity Tables (PAATs).

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

Updated: 2025-10-16

Drug Identification Number (DIN):

  • DIN 02500833 - 50 mg ripretinib, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 278324

2023-08-18

Issued NOC 2024-07-09

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 268000

2022-09-20

Issued NOC 2023-03-16

Submission filed as a Level I – Supplement to add a manufacturing site for the drug substance. The information was reviewed and considered acceptable and an NOC was issued.

SNDS # 252308

2021-04-30

Issued NOC 2022-05-10

Submission filed as a Level I – Supplement to update the PM with new safety information from a Phase I DCC-2618-01-006 clinical study and a physiologically based pharmacokinetic modelling (PBPK) study. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 255882

2021-08-19

Issued NOC 2022-03-30

Submission filed as a Level I – Supplement to add a manufacturing site for the drug substance. The information was reviewed and considered acceptable and an NOC was issued.

Drug product (DIN 02500833) market notification

Not applicable

Date of first sale 2020-12-10

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 234688

2019-12-23

Issued NOC 2020-06-19

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Qinlock

Date SBD issued: 2020-09-22

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

Ripretinib

Drug Identification Number (DIN):

  • DIN 02500833 - 50 mg tablet, oral administration

Deciphera Pharmaceuticals, LLC

New Drug Submission Control Number: 234688

 

On June 19, 2020, Health Canada issued a Notice of Compliance to Deciphera Pharmaceuticals, LLC for the drug product Qinlock.

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 Qinlock is favourable for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with imatinib, sunitinib, and regorafenib.

Qinlock should be prescribed and supervised by a qualified health care professional who is experienced in the use of anticancer medicinal products.

 

1 What was approved?

 

Qinlock, an antineoplastic agent, was authorized for the treatment of adult patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with imatinib, sunitinib, and regorafenib.

Qinlock should be prescribed and supervised by a qualified health care professional who is experienced in the use of anticancer medicinal products.

No data are available to Health Canada regarding the use of Qinlock in pediatric patients (<18 years of age). Therefore, it is not authorized for use in this population.

Limited clinical data are available regarding the use of Qinlock in geriatric patients (≥65 years of age). Although data are limited, no clinically important differences in safety or efficacy were observed between patients 65 years of age or older and patients under 65 years.

Qinlock is contraindicated in patients who are hypersensitive to the medicinal ingredient, ripretinib, or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.

Qinlock 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.

Qinlock (50 mg ripretinib) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains crospovidone, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and silicon dioxide.

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

 

2 Why was Qinlock approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Qinlock is favourable for the treatment of adult patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with imatinib, sunitinib, and regorafenib.

Qinlock should be prescribed and supervised by a qualified health care professional who is experienced in the use of anticancer medicinal products.

Gastrointestinal stromal tumours are the most common form of soft tissue sarcoma, a relatively rare subset of cancers arising from the mesenchymal cells in the body. They occur mainly in older patients, with an annual incidence of 11.0 to 19.6 people per one million people worldwide. Approximately 500 cases of GIST are diagnosed in Canada each year.

Primary mutations in GISTs are most often located in the receptor tyrosine kinase (KIT) proto‑oncogene (80‑85% of cases), and less frequently, in the platelet derived growth factor receptor A (PDGFRA) kinase (5‑10% of cases). These mutations disrupt the autoinhibited forms of KIT and PDGFRA kinases, causing uncontrolled cell growth and transformation, ultimately leading to tumour growth and metastasis. The most common sites of metastasis are the liver and abdominal membranes.

The prognosis for patients with GIST depends on the size, mitotic rate, location, and mutation status of the tumour at the time of diagnosis. Surgical resection is the only potentially curative treatment, but is associated with a 50% recurrence rate. Radiotherapy and traditional chemotherapy are not effective against advanced GIST. On average, the 5‑year survival rate is 54%, and the disease‑free survival rate is 45%, with lower rates for patients in higher risk categories.

Prior to the approval of KIT‑targeted therapies, the median survival rate for metastatic GIST was 14 to 19 months. At the time of authorization of Qinlock, three tyrosine kinase inhibitors (imatinib mesylate, sunitinib malate, and regorafenib) were approved in Canada for the treatment of advanced GIST. There were no further options for patients who experienced disease progression following treatment with each of the three approved drugs. Qinlock is a fourth‑line treatment option for patients with metastatic or unresectable GIST.

The clinical efficacy of Qinlock was demonstrated primarily through the randomized, pivotal Phase III study, INVICTUS (DCC‑2618‑03‑001). Patients enrolled in this study had unresectable, locally advanced or metastatic GISTs and had previously been treated with imatinib mesylate, sunitinib malate, and regorafenib. The study was placebo‑controlled, as there was no fourth‑line treatment available for patients with advanced GISTs at the time of study initiation. Individual participant blinding was broken at the time of disease progression, at which point patients originally in the placebo arm were offered the option to receive treatment with Qinlock.

The primary efficacy endpoint, progression‑free survival (PFS), was achieved with a PFS hazard ratio of 0.15 (95% confidence interval: 0.09, 0.25, p‑value <0.0001). The median PFS was 6.3  months in the Qinlock arm (95% CI: 4.6, 6.9), and 1.0 month in the placebo arm (95% CI: 0.9, 1.74). At 26 weeks, the estimated PFS rate was 51.0% in the Qinlock arm and 3.2% in the placebo arm.

The safety profile of Qinlock was characterized based on data from the INVICTUS study as well as a supportive Phase I study (DCC‑2816‑01‑001).

In the INVICTUS study, the most common adverse events (≥20%) observed in patients treated with Qinlock (all grades) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar‑plantar erythrodysesthesia syndrome, and vomiting. Serious adverse events occurred in 31% of patients who received Qinlock. The serious adverse reactions that occurred in >2% of patients were abdominal pain (4.7%), anemia (3.5%), nausea (2.4%), and vomiting (2.4%). The serious adverse events considered to be drug-related were anemia, cardiac failure, death, dyspnea, fecaloma, gastroesophageal reflux disease, hyperkaliemia, hypophosphatasemia, nausea, and upper gastrointestinal hemorrhage; all of which were reported in one patient (1.2%) each.

The supportive Phase I study (DCC‑2816-01-001) was conducted in patients with different types of malignancies, including GIST, who received at least one dose of Qinlock regardless of the dosage strength or the type of cancer. Common adverse events included anemia, alopecia, fatigue, myalgia, arthralgia, muscle spasms, headache, dyspnea, constipation, nausea, abdominal pain, diarrhea, vomiting, stomatitis, peripheral edema, asthenia, decreased weight, decreased appetite, dry skin, pruritus, hypertension and palmar‑plantar erythrodysaesthesia syndrome.

A Serious Warnings and Precautions box in the Qinlock Product Monograph highlights the risks of cardiac dysfunction, hypertension, and new primary cutaneous malignancies (squamous cell carcinoma and melanoma), which are clinically significant adverse events. It additionally states that only qualified healthcare professionals who are experienced in the use of anticancer medicinal products should prescribe and supervise treatment with Qinlock.

A Risk Management Plan (RMP) for Qinlock was submitted by Deciphera Pharmaceuticals, LLC 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 Qinlock Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Qinlock was accepted.

Qinlock has an acceptable safety profile based on the non‑clinical and clinical studies. The identified safety issues can be managed through labelling, adequate monitoring, and dose adjustments. Appropriate warnings and precautions are in place in the Qinlock Product Monograph to address the identified safety concerns.

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 Qinlock?

 

The New Drug Submission (NDS) for Qinlock was reviewed under Project Orbis. Project Orbis provides a framework for concurrent submission and review of oncology products as well as information sharing among regulators from multiple jurisdictions. Health Canada, the United States Food and Drug Administration (FDA), and the Australian Therapeutic Goods Administration (TGA) participated in the review of the NDS for Qinlock. Although the review of the submission was collaborative, each jurisdiction made their regulatory decision independently. The Canadian regulatory decision on the review of Qinlock was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the FDA were used as an added reference.

Due to the collaborative nature of submissions reviewed under Project Orbis and the need to align submission filing dates as closely as possible with international regulatory partners, Health Canada allowed Deciphera Pharmaceuticals, LLC to submit the NDS for Qinlock while the Priority Review request was still under consideration.

The NDS for Qinlock was reviewed under the Priority Review Policy. The NDS for Qinlock met the criteria for Priority Review Status, as substantial evidence of clinical effectiveness was provided for the treatment of a disease that is not adequately managed by drugs marketed in Canada. Radiotherapy and traditional chemotherapy are not effective against advanced gastrointestinal stromal tumours (GIST). Following treatment with the three tyrosine kinase inhibitors currently authorized for use in advanced GIST in Canada, there were no further treatment options for patients with advanced GISTs who experienced disease progression. The submitted data showed that Qinlock provides a meaningful benefit in delaying disease progression or death as a fourth‑line treatment for patients with advanced GISTs, with an acceptable safety profile.

 

Submission Milestones: Qinlock

Submission Milestone Date
Request for priority status  
Filed: 2019-12-04
Approval issued by Director, Bureau of Medical Sciences: 2020-01-07
Submission filed: 2019-12-23
Screening  
Screening Deficiency Notice issued: 2020-01-13
Response filed: 2020-01-30
Screening Acceptance Letter issued: 2020-03-11
Review  
Biostatistics Evaluation complete: 2020-04-22
Review of Risk Management Plan complete: 2020-05-13
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-05-15
Quality Evaluation complete: 2020-06-09
Clinical/Medical Evaluation complete: 2020-06-18
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2020-06-19

 

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.

 

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

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 decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Qinlock 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

Ripretinib, the medicinal ingredient in Qinlock, is a tyrosine kinase inhibitor that inhibits the receptor tyrosine kinase (KIT) proto‑oncogene and signalling by the platelet‑derived growth factor receptor A (PDGFRA) kinase. Ripretinib inhibits KIT and PDGFRA kinase activity, including wild type and multiple primary and secondary mutations. Ripretinib also inhibits other kinases in vitro, such as PDGFRB, tunica interna endothelial kinase 2 (TIE2), vascular endothelial growth factor receptor 2 (VEGFR2), and the BRAF proto‑oncogene.

The pharmacokinetics of Qinlock and its primary metabolite, DP‑5439, were evaluated following the administration of single doses of Qinlock to healthy subjects and multiple doses to patients with advanced malignancies. Doses of up to 250 mg once daily and 200 mg twice daily were administered to patients with advanced malignancies.

Exposure was evaluated based on the maximum concentration (Cmax) and the systemic exposure in the first 24 hours following administration, as measured by the area under the concentration‑time curve (AUC0‑24). Exposure to ripretinib, the medicinal ingredient in Qinlock, was dose proportional from 20 mg to 150 mg, and less than dose proportional above this range. Exposure to DP‑5439 was less than dose proportional within the 20 mg to 250 mg range. With once daily doses of 150 mg ripretinib, steady state was achieved by Day 15. Ripretinib and DP‑5439 accumulated with geometric mean ratios of 1.66 (55.3% coefficient of variation [CV]) and 5.29 (48.7% CV), respectively, based on AUC.

Qinlock may be taken with or without food. A high‑fat, high‑calorie meal administered to patients before a 150 mg dose of ripretinib increased the exposure of ripretinib and DP‑5439 when compared to dose administration under modified fasting conditions. However, the increase in exposure was not considered clinically relevant. Qinlock was administered without regard to food in the pivotal and supportive studies.

Ripretinib is metabolized primarily by cytochrome P450 (CYP) 3A4/5. The major metabolite, DP‑5439, has similar potency and is present in a 1:1 ratio relative to ripretinib. After a single 150 mg dose in healthy subjects, the mean half‑life (t½) was 14.8 hours for ripretinib and 17.8 hours for DP‑5439.

Patients treated with ripretinib and a strong CYP3A inhibitor concomitantly should be monitored more frequently for adverse reactions. Concomitant administration of ripretinib with a strong CYP3A inhibitor increased the exposure to ripretinib and DP‑5439, as measured by both the area under the concentration‑time curve (AUC0‑∞; by 99% each for ripretinib and DP‑5439) and the Cmax (by 36% for ripretinib and 6% for DP‑5439). However, based on the demonstrated tolerable safety profile of ripretinib, dose adjustment is not needed.

Concomitant use of ripretinib with a strong CYP3A inducer should be avoided. Ripretinib and DP‑5439 are both metabolized by CYP3A, and reduced exposure may result in decreased efficacy based on the exposure‑response analysis.

In an uncontrolled Phase I study in patients with advanced malignancies, administration of ripretinib did not cause a large mean increase in QTc interval (i.e., >20 ms) relative to baseline values.

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

Clinical Efficacy

Evidence of the clinical efficacy of Qinlock is based primarily on the results of the INVICTUS study (DCC‑2618‑03‑001), a pivotal, Phase III study conducted in patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumour (GIST). Prior to enrollment, patients had been previously treated with imatinib mesylate, sunitinib malate, and regorafenib.

Patients were randomized in a 2:1 ratio to receive either 150 mg Qinlock (number of patients [n] = 85) or placebo (n = 44), which were administered orally once per day, in consecutive 28‑day cycles. This study was placebo‑controlled, as there is currently no authorized fourth‑line treatment for patients with advanced GIST. Randomization was stratified by the number of prior anticancer treatments (3 versus ≥4) and by Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1 or 2). Treatment continued until patients experienced disease progression or an unacceptable level of toxicity. Individual participant blinding was broken at the time of disease progression (as assessed by blinded independent central review [BICR]). At this point, all patients originally in the placebo arm were offered the option to cross over to treatment with Qinlock.

The primary efficacy endpoint, progression‑free survival (PFS), was achieved with a hazard ratio of 0.15, stratified log‑rank test p<0.0001. The median PFS was 6.3 months in the Qinlock arm (95% confidence interval [CI]: 4.6, 6.9), and 1.0 month in the placebo arm (95% CI: 0.9, 1.74). At 26 weeks, the estimated PFS rate was 51.0% in the Qinlock arm and 3.2% in the placebo arm. Sensitivity analyses were also conducted, and produced results consistent with the primary analysis for PFS. For the primary analysis, progression‑free survival was based on disease assessment by BICR, using modified Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. In the modified criteria, lymph nodes and bone lesions were not target lesions, and a progressively growing new tumour nodule with a pre‑existing tumour mass had to meet specific criteria to be considered unequivocal evidence of progression.

The key secondary endpoints were objective response rate (ORR) assessed by BICR, and overall survival (OS). The hierarchical order for statistical testing was PFS, followed by ORR, and then OS. A confirmed ORR of 9.4% was reported for ripretinib compared with 0% for placebo. The results of the analysis of ORR failed to reach statistical significance (p = 0.0504). Therefore, formal testing of the OS could not be conducted. The hazard ratio for OS was 0.36 with a median OS of 15.1 months for ripretinib compared to 6.6 months for placebo. Overall survival results for patients in the placebo arm include survival time of patients who originally received the placebo, and crossed over to the Qinlock treatment arm following disease progression. At the time of final analysis, 29 patients (65.9%) had crossed over and received at least one dose of Qinlock.

Indication

Sponsor's proposed indication Health Canada-approved indication
Qinlock (ripretinib) is a kinase inhibitor indicated for:
  • the treatment of patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with imatinib, sunitinib, and regorafenib.
 Qinlock (ripretinib) is indicated for:
  • the treatment of adult patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with imatinib, sunitinib, and regorafenib.
Qinlock should be prescribed and supervised by a qualified health care professional who is experienced in the use of anticancer medicinal products.

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

Clinical Safety

The safety profile of Qinlock was characterized based on data from the pivotal INVICTUS study, described in the Clinical Efficacy section, and the supportive Phase I study (DCC2816‑01‑001).

The safety population from the INVICTUS study consisted of 128 patients who had received at least one dose of either Qinlock or placebo. Although 129 patients were initially enrolled in this study, one patient randomized to the placebo arm did not receive treatment. The clinical safety data were collected during the double‑blind period of the study, during which the median duration of exposure was 23.9 weeks (range: 1.3 to 59.4 weeks), and 45.9% of patients received Qinlock for six months or longer.

The common adverse events (≥10%) observed in patients treated with Qinlock (all grades) were alopecia, fatigue, arthralgia, muscle spasms, headache, dyspnea, abdominal pain, stomatitis, peripheral edema, asthenia, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased weight, decreased appetite, dry skin, pruritus, hypertension, palmar‑plantar erythrodysesthesia syndrome, and vomiting.

Serious adverse events occurred in 31% of patients who received Qinlock. The serious adverse reactions that occurred in >2% of patients were abdominal pain (4.7%), anemia (3.5%), nausea (2.4%), and vomiting (2.4%). The serious adverse events considered to be drug‑related were anemia, cardiac failure, death, dyspnea, fecaloma, gastroesophageal reflux disease, hyperkaliemia, hypophosphatasemia, nausea, and upper gastrointestinal hemorrhage; all of which were reported in one patient (1.2%) each.

The supportive Phase I study (DCC‑2816‑01‑001) was conducted in patients with different types of malignancies, including GIST. In this study, 184 patients with GIST received Qinlock at doses that ranged from 20 mg twice daily up to 200 mg twice daily, with 83 patients with GIST receiving 150 mg once daily as a fourth line treatment or above.

Pooled safety data collected from 351 patients (combined patients of the INVICTUS and Phase I studies) who received at least one dose of Qinlock, regardless of the dosage strength or the type of cancer, was also assessed. Cases of keratoacanthoma and hypersensitivity were reported. Common adverse events (≥10%) included anemia, alopecia, fatigue, myalgia, arthralgia, muscle spasms, headache, dyspnea, constipation, nausea, abdominal pain, diarrhea, vomiting, stomatitis, peripheral edema, asthenia, decreased weight, decreased appetite, dry skin, pruritus, hypertension, increased lipase, cough, back pain, increased blood bilirubin, dizziness, hypokalemia, hypophosphatemia, rash, actinic keratosis, pain in extremities, and palmar‑plantar erythrodysaesthesia syndrome.

A Serious Warnings and Precautions box in the Qinlock Product Monograph highlights the risks of cardiac dysfunction, hypertension, and new primary cutaneous malignancies (squamous cell carcinoma and melanoma), which are clinically significant adverse events. It additionally states that only qualified healthcare professionals who are experienced in the use of anticancer medicinal products should prescribe and supervise treatment with Qinlock.

Qinlock was generally well tolerated. The adverse events, including the serious adverse events, can be addressed as needed through adequate monitoring, and dose reduction, interruption or discontinuation.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Qinlock, and to promote their safe and effective use. Overall, the benefit‑harm‑uncertainty profile of Qinlock is favourable for the approved indication.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Ripretinib, the medicinal ingredient in Qinlock, inhibited receptor tyrosine kinase (KIT) and platelet derived growth factor receptor A (PDGFRA) kinases in vitro, generally exhibiting high degrees of potency against many mutant forms of both types of kinases.

Both ripretinib and its primary active metabolite, DP‑5439, blocked the cellular proliferation or phosphorylation by KIT/PDGFRA in gastrointestinal stromal tumour (GIST), acute myeloid leukemia (AML), and mastocytosis cell lines driven by mutations in KIT. Ripretinib and DP‑5439 also induced apoptosis in KIT mutant mast cells and prevented the emergence of drug resistance in KIT mutant cellular saturation mutagenesis assays. In cellular assays, ripretinib and DP‑5439 also inhibited several key kinases involved in the tumor microenvironment. High selectivity was observed for the KIT family kinases.

Tumour regression was observed in vivo in mouse models, including complete tumour regression in some cases, with slow regrowth after treatment cessation. An additive effect on tumour regression was observed when ripretinib was administered in combination with other agents. Off‑target activity appeared to be minimal at clinically relevant exposures.

In repeat‑dose studies, growing incisor teeth were either missing or discoloured in rats, and discoloured skin, skin lesions, and alopecia/thinning hair coat were observed in rats and dogs. Decreased food consumption and decreased body weight and body weight gain were also observed. During the recovery phase, the development of scaly skin, thinning hair coat, or sores and scabs were found to be reversible. In rats, signs of toxicity were also observed in the bones and spleen at doses of ≥30 mg/kg/day, and minimal to moderate effects were observed in blood vessels in the liver, lungs, and/or mesenteric lymph nodes at doses of ≥100 mg/kg/day. Adverse effects were observed in the gastrointestinal tract in female rats at a dose of 300 mg/kg/day.

Safety pharmacology studies in dogs showed significant, dose‑dependent increases in heart rate. This was observed at exposures similar to the clinical exposure in humans, for both ripretinib and DP‑5439. Secondary decreases in the QT and PR intervals were also detected. No effects were observed on the respiratory or central nervous systems.

Ripretinib is metabolized primarily by cytochrome P450 (CYP) 3A4/5, CYP2C8, and CYP2D6. Further metabolism of DP‑5439 is done primarily by CYP3A4 and CYP2D6. There is potential for CYP‑mediated drug‑drug interactions based on the inhibition potential for ripretinib and DP‑5439.

Ripretinib was significantly teratogenic in rats, at exposures similar to the expected exposure in humans at the recommended clinical dose. Dose‑related malformations were observed during an embryo‑fetal development study in pregnant rats, in which ripretinib was administered during organogenesis (gestational days 6 through 18). Malformations affecting the cardiovascular and skeletal systems were observed at a maternal dose of 20 mg/kg/day (corresponding to approximately half the expected exposure at the recommended dose). Anatomic variations, which are signs of developmental toxicity, were observed at an increased incidence at a dose of 20 mg/kg/day. Reduced fetal body weight and reduced ossification sites in fetuses were also observed at this dose.

When administered to pregnant rabbits (once daily from gestational days 7 through 19), increased post‑implantation loss and reduced fetal body weights were observed at a dose of 40 mg/kg/day. Ripretinib‑related abortions and maternal body weight loss were observed at a dose of 150 mg/kg/day. It is unknown whether ripretinib is excreted in milk.

Although no dedicated fertility studies were conducted in male animals, adverse effects were observed in reproductive organs in repeat‑dose toxicity studies in male rats. Ripretinib‑related bilateral degeneration/atrophy of the testis and increased cellular debris of the epididymis were observed at doses of 30 and 300 mg/kg/day. Corresponding decreases in testis and epididymis weights were also observed at these doses, and were not reversed by the end of the recovery period.

Ripretinib was not found to be genotoxic. Carcinogenicity studies were not conducted for ripretinib, as they were not required by the relevant International Council for Harmonisation (ICH) guidelines. In in vitro studies, ripretinib exhibited high potential for phototoxicity at clinically relevant concentrations following exposure to ultraviolet A and B radiation.

The results of the non‑clinical studies as well as the potential risks to humans are addressed in detail in the Qinlock Product Monograph. Appropriate warnings and precautionary measures have also been included to address the identified safety concerns. Considering the intended use of Qinlock, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Qinlock 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 Qinlock 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 18 months is acceptable when the drug product is stored in its original container at room temperature (15ºC to 25ºC).

Proposed limits of drug‑related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits).

All sites involved in production 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.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.

 

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