DKN-01 for Colorectal Cancer

(DeFianCe Trial)

No longer recruiting at 54 trial locations

Overseen By Cynthia Sirard, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Leap Therapeutics, Inc.

Must not be taking: Anti-DKK1, PD-1, others

Disqualifiers: MSI-H/dMMR, BRAF V600E, others

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

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: approximately 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a new treatment, DKN-01 (a DKK1-neutralizing monoclonal antibody), for individuals with advanced colorectal cancer compared to standard treatments. Participants will receive either DKN-01 combined with standard chemotherapy and bevacizumab (Avastin) or the standard treatments alone. The study targets patients whose cancer has progressed after initial treatment. Those with advanced colorectal cancer that has advanced following initial chemotherapy may qualify for this trial. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot have had systemic anti-cancer therapy within 28 days before starting the study drug.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that DKN-01, also known as sirexatamab, was tested in earlier studies to assess its safety. In these studies, researchers combined it with other treatments like bevacizumab and standard chemotherapy (FOLFIRI or FOLFOX). Results indicated that DKN-01 was generally well-tolerated, with most patients not experiencing severe side effects.

Although specific details about side effects are not provided, the progression of DKN-01 to this study phase suggests it demonstrated an acceptable safety level in earlier research. Bevacizumab, already FDA-approved for other uses, has a well-known safety record, though it can cause side effects like high blood pressure and an increased risk of bleeding.

Overall, combining DKN-01 with these treatments appears safe for most people, based on earlier study data. However, like any treatment, side effects can occur, so participants should discuss potential risks with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about DKN-01 for colorectal cancer because it targets a specific pathway called DKK1, which is different from the traditional chemotherapy and bevacizumab options. This unique mechanism of action could potentially enhance the effectiveness of existing treatments like FOLFIRI or FOLFOX when combined with bevacizumab. By focusing on this new target, DKN-01 may offer an innovative approach to overcoming resistance to standard therapies and improving outcomes for patients.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

Research has shown that DKN-01, also known as sirexatamab, holds promise in treating colorectal cancer (CRC). In this trial, some participants will receive DKN-01 combined with FOLFIRI or FOLFOX and bevacizumab. One study found that 35% of patients who received DKN-01 with bevacizumab experienced tumor shrinkage. DKN-01 targets the Dickkopf-1 (DKK1) protein, which is believed to aid cancer growth, particularly in patients with high DKK1 levels who typically have worse outcomes. These findings suggest that DKN-01 could be a valuable addition to current treatments for advanced CRC. ^{1 2 5 6 7}

Who Is on the Research Team?

Cynthia Sirard

Principal Investigator

Leap Therapeutics, Inc.

Are You a Good Fit for This Trial?

Adults with advanced colorectal cancer (CRC) who've seen their disease progress after one line of systemic treatment. They must not have had certain prior treatments depending on the trial group they're assigned to, and should be in good physical condition (ECOG ≤1). Participants need measurable tumors and adequate organ function. Women of childbearing age and male partners must use contraception.

Inclusion Criteria

My cancer progressed after first-line treatment with a fluoropyrimidine-based regimen.

I have previously received anti-VEGF or anti-EGFR therapy.

I agree to use birth control during and for 6 months after the study.

Exclusion Criteria

I have not had radiation therapy in the last 14 days.

I do not have severe heart disease, recent heart attack, or irregular heartbeat.

Significant allergy to a pharmaceutical therapy that, in the opinion of the Investigator, poses an increased risk to the patient

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive DKN-01 plus FOLFIRI/FOLFOX and bevacizumab or standard of care (SOC) as second-line treatment

approximately 6 months

Safety Follow-up

Participants are monitored for safety approximately 30 days after the last administration of study drug

4-5 weeks

Long-Term Follow-up

Participants are followed for survival, subsequent therapies, and disease progression if applicable

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• DKN-01
• FOLFIRI
• FOLFOX

Trial Overview The study is testing DKN-01 in combination with chemotherapy regimens FOLFIRI or FOLFOX plus bevacizumab against standard care for second-line treatment of CRC. It's a Phase 2 trial where patients are randomly chosen to receive either the test combo or the standard therapy.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 4 Interventions

DKN-01 + FOLFIRI or FOLFOX + bevacizumab

Group II: Control Active Control 3 Interventions

FOLFIRI or FOLFOX + bevacizumab

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Leap Therapeutics, Inc.

Lead Sponsor

Trials

16

Recruited

1,100+

Published Research Related to This Trial

Metastatic colorectal cancer (CRC) patients showed significantly lower immune responses at baseline compared to healthy donors, but these responses improved during treatment with either irinotecan/5-fluorouracil/leucovorin (IFL) or IFL combined with bevacizumab (B-IFL).

The combination of IFL with bevacizumab (B-IFL) resulted in greater increases in key immune markers (like IL-2 and IFN-γ) compared to IFL alone, suggesting that B-IFL may enhance immune function in CRC patients during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined treatment with bevacizumab and standard chemotherapy restores abnormal immune parameters in advanced colorectal cancer patients. Tsavaris, N., Voutsas, IF., Kosmas, C., et al.[2021]

Bevacizumab, a monoclonal antibody that blocks vascular endothelial growth factor, significantly improved response rates and survival in metastatic colorectal cancer when combined with chemotherapy, based on a randomized phase III trial.

Cetuximab, which inhibits the epidermal growth factor receptor, demonstrated a 22.5% response rate and prolonged progression-free survival in irinotecan-refractory patients, highlighting its effectiveness as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Which role do new therapeutic options play in palliative care of colorectal cancer?]. Verbeek, W., Graeven, U.[2018]

In a phase II trial involving 209 patients with metastatic colorectal cancer, the addition of bevacizumab to fluorouracil and leucovorin (FU/LV) significantly improved median progression-free survival to 9.2 months compared to 5.5 months with placebo, indicating a strong therapeutic benefit.

While bevacizumab treatment was associated with a higher incidence of grade 3 hypertension (16% vs. 3% in the placebo group), this side effect was manageable with medication and did not lead to discontinuation of the treatment, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. Kabbinavar, FF., Schulz, J., McCleod, M., et al.[2022]

In a study involving 27 heavily pretreated patients with metastatic colorectal cancer, the combination of irinotecan, cetuximab, and bevacizumab was well tolerated and resulted in a progression-free survival (PFS) of 8.3 months and a median overall survival (mOS) of 12.0 months.

The addition of bevacizumab to the treatment regimen showed a trend towards improved outcomes in patients without KRAS mutations, suggesting that this combination therapy may be particularly effective for certain patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in combination with cetuximab and irinotecan after failure of cetuximab and irinotecan in patients with metastatic colorectal cancer. Larsen, FO., Pfeiffer, P., Nielsen, D., et al.[2018]

In a combined analysis of three studies involving 490 patients, the addition of bevacizumab to FU/LV treatment resulted in a median overall survival of 17.9 months, compared to 14.6 months for the control group, indicating a significant survival benefit.

Patients receiving FU/LV with bevacizumab also experienced improved progression-free survival (8.8 months vs. 5.6 months) and a higher response rate (34.1% vs. 24.5%), demonstrating the efficacy of bevacizumab in treating metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. Kabbinavar, FF., Hambleton, J., Mass, RD., et al.[2022]

Citations

1. investors.leaptx.com investors.leaptx.com/news-releases/news-release-details/leap-therapeutics-reports-updated-clinical-data-sirexatamab

News Release - Investors - Leap Therapeutics Updated data from DeFianCe study continue to demonstrate statistically significant improvements in PFS among the DKK1 -high, VEGF-naïve and ...

2. investors.leaptx.com investors.leaptx.com/node/10086/pdf

Positive Updated Data from Sirexatamab Colorectal Cancer ... Leap's most advanced clinical candidate, sirexatamab (DKN-01), is a humanized monoclonal antibody targeting the Dickkopf-1 (DKK1) protein.

3. firstwordpharma.com firstwordpharma.com/story/6326356

Leap Therapeutics Presents Final Data from DeFianCe ... Patients with this aggressive cancer, particularly those with high DKK1 levels, have poor overall survival outcomes and few promising second- ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05480306

Phase 2 Study of DKN-01 in Colorectal Cancer (DeFianCe) This is a Phase 2 randomized, open-label, two-part, multicenter study with a safety run-in to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and ...

5. leaptherapeutics.gcs-web.com leaptherapeutics.gcs-web.com/news-releases/news-release-details/leap-therapeutics-reports-initial-clinical-data-part-b-defiance

Leap Therapeutics Reports Initial Clinical Data from Part B of ... 35% objective response rate (ORR) in second-line colorectal cancer (CRC) patients treated with sirexatamab (DKN-01) plus bevacizumab and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05480306

Phase 2 Study of DKN-01 in Colorectal Cancer (DeFianCe) This is a Phase 2 randomized, open-label, two-part, multicenter study with a safety run-in to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and ...

7. cancernetwork.com cancernetwork.com/view/sirexatamab-combo-shows-positive-activity-in-advanced-mss-colorectal-cancer

Sirexatamab Combo Shows Positive Activity in Advanced ... Sirexatamab plus bevacizumab/chemotherapy significantly improved overall response rate in patients with high DKK1 levels in the phase 2 DeFianCe study.