Ripretinib vs Sunitinib for Gastrointestinal Stromal Tumors

(INTRIGUE Trial)

Recruiting at 119 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Deciphera Pharmaceuticals, LLC

Must not be taking: BCRP inhibitors

Disqualifiers: CNS metastases, Heart disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 6 weeks per cycle

453 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a 2-arm, randomized, open-label, international, multicenter study comparing the efficacy of ripretinib to sunitinib in GIST patients who progressed on or were intolerant to first-line anticancer treatment with imatinib. Approximately 426 patients will be randomized in a 1:1 ratio to ripretinib 150 mg once daily (continuous dosing for 6 week cycles) or sunitinib 50 mg once daily (6 week cycles, 4 weeks on, 2 weeks off).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use certain drugs that affect specific proteins (BCRP transporters) within 14 days before starting the study drug. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug ripretinib compared to sunitinib for gastrointestinal stromal tumors?

The INTRIGUE trial found that ripretinib is not more effective than sunitinib in terms of progression-free survival for gastrointestinal stromal tumors, but it has a better safety profile with fewer severe side effects. ^{1 2 3 4 5}

Is Ripretinib or Sunitinib safe for treating gastrointestinal stromal tumors?

Ripretinib generally has a better safety profile than Sunitinib, causing fewer severe side effects like high blood pressure. Sunitinib is approved for use but can have significant side effects that need to be managed to maintain quality of life. ^{2 6 7 8 9}

What makes ripretinib unique compared to other drugs for gastrointestinal stromal tumors?

Ripretinib is unique because it is a switch-control tyrosine kinase inhibitor designed to target both primary and secondary resistance mutations in KIT and PDGFRA, which can develop after treatment with other drugs. It also has a better safety profile with fewer severe side effects compared to sunitinib. ^{1 2 3 10 11}

Eligibility Criteria

This trial is for adults over 18 with Gastrointestinal Stromal Tumors (GIST) who've had issues with the first-line treatment, imatinib. They need a confirmed diagnosis and must provide tissue samples for testing. Participants should be relatively fit (ECOG PS ≤2), not pregnant, willing to use contraception, have at least one measurable tumor lesion, and stable organ function.

Inclusion Criteria

If you can have children, you must agree to use birth control as detailed in the study rules.

I have a tumor that can be measured by scans.

I have a GIST diagnosis and can provide a past or new tumor sample.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ripretinib or sunitinib in 6-week cycles

6 weeks per cycle

Continuous dosing for ripretinib; 4 weeks on, 2 weeks off for sunitinib

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2.1 years

Treatment Details

Interventions

• DCC-2618
• Sunitinib

Trial Overview The study compares two drugs: Ripretinib taken daily in continuous 6-week cycles versus Sunitinib taken daily for 4 weeks on/2 weeks off in similar cycles. It's designed to see which drug works better after imatinib fails in advanced GIST patients.

Participant Groups

Group I: Ripretinib Experimental Treatment 1 Intervention

Ripretinib (150 mg) once a day continuous dosing for 6-week (42 days) cycles

Group II: Sunitinib Active Control 1 Intervention

Sunitinib (50 mg) once a day in 6-week (42 days) cycles with 4 weeks continuous dosing followed by 2 week break.

Who Is Running the Clinical Trial?

Deciphera Pharmaceuticals, LLC

Lead Sponsor

Trials

19

Recruited

2,100+

Deciphera Pharmaceuticals LLC

Lead Sponsor

Trials

17

Recruited

1,900+

Findings from Research

Ripretinib is a new type II tyrosine switch control inhibitor that targets both activating and drug-resistant mutations in KIT and PDGFRA, making it a promising treatment for gastrointestinal stromal tumors, especially after previous treatments with other tyrosine kinase inhibitors.

The ongoing Phase III study (NCT03673501) is comparing the safety and efficacy of ripretinib to sunitinib in patients with advanced gastrointestinal stromal tumors, focusing on progression-free survival as the primary endpoint.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Nemunaitis, J., Bauer, S., Blay, JY., et al.[2020]

In the phase III INTRIGUE trial, ripretinib was found to be not superior to sunitinib for progression-free survival in patients with gastrointestinal stromal tumors.

Ripretinib demonstrated a better safety profile, resulting in fewer severe side effects (grade 3-4 toxicities), including lower rates of hypertension compared to sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testing Ripretinib against Sunitinib in GIST. [2022]

In the INTRIGUE trial, patients with advanced gastrointestinal stromal tumors (GIST) treated with ripretinib reported better health-related quality of life (HRQoL) compared to those treated with sunitinib, particularly at the 29-day assessments.

Patients receiving ripretinib also experienced a longer time without symptoms or severe treatment-related side effects, averaging 173 days compared to 126 days for those on sunitinib, suggesting ripretinib may offer a clinically meaningful benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study. Gelderblom, H., Jones, RL., Blay, JY., et al.[2023]

Sunitinib malate significantly improves time to progression and progression-free survival in adult patients with gastrointestinal stromal tumors (GIST) who are resistant or intolerant to imatinib, with a hazard ratio for overall survival of 0.49, indicating a substantial benefit over placebo.

While sunitinib malate is effective, it is associated with a higher incidence of hematologic adverse effects such as leucopenia and neutropenia, as well as other side effects like fatigue and hand-foot syndrome, suggesting that while it is a recommended second-line therapy, monitoring for these adverse effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate-resistant patients: recommendations and evidence. Younus, J., Verma, S., Franek, J., et al.[2021]

Sunitinib malate (Sutent) was approved by the FDA for treating gastrointestinal stromal tumors (GIST) after patients showed disease progression or intolerance to imatinib, demonstrating a median time-to-tumor progression of 27.3 weeks compared to 6.4 weeks for placebo.

In advanced renal cell carcinoma, sunitinib showed partial response rates of 25.5% and 36.5% in two studies, with median response durations of 27.1 and 54 weeks, although it was associated with common side effects like diarrhea and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Goodman, VL., Rock, EP., Dagher, R., et al.[2022]

Sunitinib malate has shown long-term efficacy and safety in treating metastatic renal cell carcinoma (mRCC) and advanced imatinib-refractory gastrointestinal stromal tumors (GIST), as demonstrated in four patient cases.

Effective management of adverse events (AEs) allowed patients to continue long-term therapy with sunitinib, leading to sustained clinical benefits and prolonged responses in both mRCC and GIST cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tyrosine kinase inhibition in renal cell carcinoma and gastrointestinal stromal tumours: case reports. Schöffski, P., Bukowski, R., Flodgren, P., et al.[2020]

In a study of 55 Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors (GISTs), sunitinib demonstrated effectiveness with a median overall survival of 86 weeks and a median progression-free survival of 35 weeks for those on a continuous daily dose of 37.5 mg.

Patients with KIT exon 9 mutations experienced significantly longer progression-free survival compared to those with KIT exon 11 mutations or wild-type GISTs, indicating that genetic factors can influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. Li, J., Gao, J., Hong, J., et al.[2022]

Ripretinib demonstrated a higher objective response rate compared to sunitinib in patients with advanced gastrointestinal stromal tumors (GIST) who had previously been treated with imatinib, showing 23.9% versus 14.6% respectively.

Although ripretinib was not superior to sunitinib in terms of progression-free survival (PFS), it had a significantly better safety profile with fewer severe adverse events (41.3% for ripretinib vs. 65.6% for sunitinib), indicating it may be a more tolerable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial. Bauer, S., Jones, RL., Blay, JY., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Testing Ripretinib against Sunitinib in GIST. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate-resistant patients: recommendations and evidence. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Sunitinib as a second-line therapy for advanced GISTs after failure of imatinib: relationship between efficacy and tumor genotype in Korean patients. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Tyrosine kinase inhibition in renal cell carcinoma and gastrointestinal stromal tumours: case reports. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Ripretinib in advanced gastrointestinal stromal tumors: an overview of current evidence and drug approval. [2022]