DKN-01 + Tislelizumab for Stomach Cancer

(DisTinGuish Trial)

Recruiting at 57 trial locations

Overseen By Cynthia Sirard, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Leap Therapeutics, Inc.

Must not be taking: Steroids, Immune suppressants

Disqualifiers: HER2-positive, Autoimmune diseases, Uncontrolled diabetes, 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

Compensation: Varies

Number of Visits: 21

Duration: Until disease progression or unacceptable toxicity

232 Participants Needed

Trial Summary

What is the purpose of this trial?

A Phase 2, Multicenter, Open-Label Study of DKN-01 in Combination with Tislelizumab ± Chemotherapy as First-Line or Second-Line Therapy in Adult Patients with Inoperable, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on steroids or immune suppressive drugs, you may need to stop them 14 days before starting the study.

What data supports the effectiveness of the drug DKN-01 + Tislelizumab for stomach cancer?

Research shows that Capecitabine (Xeloda), a component of the treatment, is effective in treating advanced gastric cancer and has been used successfully in other cancers like colorectal and breast cancer. It works by converting to 5-fluorouracil (5-FU) at the tumor site, enhancing drug concentration and reducing side effects. ^{1 2 3 4 5}

Is the combination of DKN-01 and Tislelizumab safe for treating stomach cancer?

The safety of Capecitabine (Xeloda), which is related to 5-fluorouracil (5-FU), has been studied in various cancers, including gastric cancer. It is generally considered safe, but like many cancer treatments, it can have side effects. Common side effects include hand-foot syndrome (redness and swelling of the hands and feet), diarrhea, and fatigue. ^{1 2 3 4 6}

What makes the drug DKN-01 + Tislelizumab unique for treating stomach cancer?

The combination of DKN-01 and Tislelizumab for stomach cancer is unique because it targets specific pathways involved in cancer growth and immune response, potentially offering a novel approach compared to existing treatments. This combination includes DKN-01, which is an antibody targeting DKK1, and Tislelizumab, an immune checkpoint inhibitor, which together may enhance the body's immune response against cancer cells. ^{7 8 9 10 11}

Research Team

Cynthia Sirard, MD

Principal Investigator

Chief Medical Officer

Eligibility Criteria

Adults with inoperable, advanced gastric or gastroesophageal cancer who haven't had previous cancer therapy (or have been treatment-free for 6+ months) can join. They must show elevated DKK1 mRNA from a biopsy and agree to contraception use. Exclusions include HER2-positive diagnosis, recent major surgery or chemo, active infections, certain heart conditions, uncontrolled diseases like diabetes, prior treatments with specific antibodies including anti-PD-1/L1/L2 or anti-DKK1 agents.

Inclusion Criteria

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

Able to provide written informed consent prior to any study-specific procedures.

I am at least 18 years old, or 19 if I'm from the Republic of Korea.

Exclusion Criteria

I have not experienced significant loss of appetite in the week before starting the study drug.

I do not have any ongoing serious infections needing treatment.

I have a serious illness that is not cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive DKN-01 in combination with tislelizumab ± chemotherapy in 21-day cycles

Until disease progression or unacceptable toxicity

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

6-12 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Capecitabine
• DKN-01
• Fluorouracil
• Leucovorin Calcium
• Oxaliplatin
• Tislelizumab

Trial Overview The trial is testing the effectiveness of DKN-01 in combination with Tislelizumab and possibly chemotherapy as first-line or second-line therapy. Patients will receive varying doses of these drugs to see how well they work together against stomach cancers that express a particular gene marker (DKK1).

Participant Groups

Group I: Part C Experimental First Line Treatment Experimental Treatment 8 Interventions

Part C experimental patients will receive DKN-01 in combination with tislelizumab and chemotherapy regimen (CAPOX or mFOLFOX6). Part C is restricted to patients who have not had prior systemic therapy for locally advanced or metastatic disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months.

Group II: Part B2 Second Line Treatment Experimental Treatment 3 Interventions

Part B patients will receive IV DKN-01 (600 mg) on Days 1 and 15 and IV tislelizumab (200 mg) on Day 1 of each 21-day cycle. Patients enrolled in Part B are required to have DKK1-high (H-score ≥ 35) G/GEJ adenocarcinoma (pre-screen biopsy) and must have had only 1 prior systemic therapy for locally advanced/metastatic disease (platinum + fluoropyrimidine-based therapy; ±HER2 therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.

Group III: Part B1 Second Line Treatment Experimental Treatment 3 Interventions

Part B patients will receive IV DKN-01 (300 mg) on Days 1 and 15 and IV tislelizumab (200 mg) on Day 1 of each 21-day cycle. Patients enrolled in Part B are required to have DKK1-high (H-score ≥ 35) G/GEJ adenocarcinoma (pre-screen biopsy) and must have had only 1 prior systemic therapy for locally advanced/metastatic disease (platinum + fluoropyrimidine-based therapy; ±HER2 therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.

Group IV: Part A First Line Treatment Experimental Treatment 5 Interventions

Part A patients will receive IV DKN-01 (300 mg) on Days 1 and 15, IV tislelizumab (200 mg) on Day 1, IV oxaliplatin (130 mg/m2) on Day 1, and oral capecitabine (1000 mg/m2 twice daily \[BID\]) on Days 1-15 of each 21-day cycle. Part A is restricted to patients who have not had prior systemic therapy for locally advanced or metastatic disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months.

Group V: Part C Control First Line Treatment Active Control 8 Interventions

Part C control patients will receive only tislelizumab in combination with chemotherapy regimen (CAPOX or mFOLFOX6). Part C is restricted to patients who have not had prior systemic therapy for locally advanced or metastatic disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months.

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

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

Leap Therapeutics, Inc.

Lead Sponsor

Trials

16

Recruited

1,100+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a study of 42 patients with advanced breast and colorectal cancer, capecitabine showed a partial response rate of 29.16% for breast cancer and 11.76% for colorectal cancer, indicating its potential efficacy in these pretreated patients.

Capecitabine was well tolerated with low toxicity levels, as most adverse reactions were mild, although 7.14% of patients experienced grade 3 hand-foot syndrome, and hypertriglyceridemia was noted in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. Stathopoulos, GP., Koutantos, J., Lazaki, H., et al.[2022]

In a phase III study involving 485 gastric cancer patients, oral doxifluridine (5'-DFUR) did not show differences in overall or disease-free survival compared to oral 5-fluorouracil (5-FU).

However, 5'-DFUR was found to be more effective in reducing peritoneal recurrence and showed better disease-free survival in patients with Stage III or IIIb gastric cancer compared to those treated with 5-FU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase III randomized study comparing oral doxifluridine and oral 5-fluorouracil after curative resection of gastric cancer. Takiguchi, N., Nakajima, N., Saitoh, N., et al.[2019]

A retrospective study of 12 patients with severe renal impairment (GFR <30 mL/min) showed that capecitabine can be safely administered with close monitoring and dose adjustments, despite previous contraindications from the manufacturer based on a small Phase II trial.

Most patients experienced only mild to moderate adverse effects, and some showed a positive response to treatment, indicating that capecitabine may still be effective in this population when managed carefully.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR Jhaveri, KD., Flombaum, C., Shah, M., et al.[2022]

In a study of 44 previously untreated patients with advanced gastric cancer, capecitabine demonstrated an objective response rate of 34% and a median overall survival of 9.5 months, indicating its efficacy as a first-line treatment.

Capecitabine was generally well tolerated, with the most common side effects being hand-foot syndrome and nausea, and severe myelosuppression was not observed, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Hong, YS., Song, SY., Lee, SI., et al.[2022]

Xeloda (capecitabine) is an oral medication designed to convert into 5-fluorouracil (5-FU) specifically within tumors, potentially increasing anti-tumor activity while reducing systemic toxicity, as shown in various phase I and II trials.

In a phase II trial for colorectal cancer, Xeloda demonstrated a response rate of 21-24% across different regimens, with good tolerability and a longer time to disease progression for the intermittent regimen, which was selected for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential of Xeloda in colorectal cancer and other solid tumors. Cassidy, J.[2017]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

In an expanded-access study involving 64 patients with HER2-positive gastric or gastroesophageal junction adenocarcinomas, trastuzumab deruxtecan (T-DXd) was administered safely, with no new safety concerns identified prior to its marketing approval in Japan.

Serious adverse events (SAEs) were reported in 26.6% of patients, with febrile neutropenia being the most common; however, drug-related SAEs led to death in only one patient, indicating a manageable safety profile for T-DXd.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. Shitara, K., Yamaguchi, K., Muro, K., et al.[2023]

Trastuzumab deruxtecan (T-DXd) is a promising HER2-targeted therapy that has shown significant anti-tumor activity in heavily pre-treated patients with HER2-positive breast and gastric cancers, and preliminary data suggest it may also be effective in HER2-positive non-small cell lung cancer (NSCLC) and colorectal cancer.

While T-DXd has an acceptable safety profile, there are concerns about serious treatment-emergent adverse events, highlighting the need for careful monitoring in clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors. Indini, A., Rijavec, E., Grossi, F.[2021]

The antibody-drug conjugate T-DM1 demonstrated greater effectiveness than trastuzumab in treating HER2-positive gastric cancer cell lines, particularly in N-87 and OE-19, and showed promising results in xenograft models with complete pathological responses in all OE-19 and half of N-87 tumors.

T-DM1 not only induced direct cancer cell death and abnormal cell division but also enhanced immune response through antibody-dependent cellular cytotoxicity (ADCC), suggesting it could be a viable treatment option for patients with trastuzumab-resistant HER2-positive gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Barok, M., Tanner, M., Köninki, K., et al.[2015]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. [2022]

2. Greece pubmed.ncbi.nlm.nih.gov

A phase III randomized study comparing oral doxifluridine and oral 5-fluorouracil after curative resection of gastric cancer. [2019]

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

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR [2022]

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

A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. [2022]

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

Potential of Xeloda in colorectal cancer and other solid tumors. [2017]

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

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. [2022]

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

Trastuzumab deruxtecan and other HER2-targeting agents for the treatment of HER2-positive gastric cancer. [2022]

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

Trastuzumab deruxtecan for the treatment of patients with HER2-positive gastric cancer. [2021]

9. Japan pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors. [2021]

11. Ireland pubmed.ncbi.nlm.nih.gov

Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. [2015]