DKN-01 for Colorectal Cancer

(DeFianCe Trial)

Recruiting at 44 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

188 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, DKN-01, combined with standard chemotherapy and bevacizumab for advanced colorectal cancer patients who didn't respond to earlier treatment. The treatment works by attacking cancer cells, blocking growth signals, and cutting off their blood supply.

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.

What data supports the effectiveness of the drug DKN-01 for colorectal cancer?

Research shows that bevacizumab, a component of the treatment, improves survival in patients with metastatic colorectal cancer when combined with chemotherapy, increasing median survival by 30% in one study. ^{1 2 3 4 5}

Is DKN-01 (also known as Bevacizumab or Avastin) safe for use in humans?

Bevacizumab (Avastin) is generally safe when used with chemotherapy for metastatic colorectal cancer, but it can cause side effects like high blood pressure, protein in urine, blood clots, wound-healing issues, bleeding, and gastrointestinal perforation. These side effects are manageable with proper medical care. ^{1 2 3 6 7}

What makes the drug DKN-01 unique for treating colorectal cancer?

DKN-01 is unique because it targets a specific protein called DKK-1, which is involved in cancer growth, and is combined with other treatments like Bevacizumab and chemotherapy to potentially improve outcomes for colorectal cancer patients. ^{1 2 3 8 9}

Research Team

Cynthia Sirard, MD

Principal Investigator

Leap Therapeutics, Inc.

Eligibility Criteria

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.

I haven't had any cancer other than this one in the last 2 years.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

References

1. United States 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Bevacizumab in the treatment of colorectal cancer. [2019]

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

Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. [2022]

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

Bevacizumab in combination with cetuximab and irinotecan after failure of cetuximab and irinotecan in patients with metastatic colorectal cancer. [2018]

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

Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Managing patients with metastatic colorectal cancer on bevacizumab. [2015]

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

Combined treatment with bevacizumab and standard chemotherapy restores abnormal immune parameters in advanced colorectal cancer patients. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

[Which role do new therapeutic options play in palliative care of colorectal cancer?]. [2018]