DKN-01 + Tislelizumab for Stomach Cancer

(DisTinGuish Trial)

No longer recruiting at 75 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of treatments, including DKN-01 (a DKK1-neutralizing monoclonal antibody) and tislelizumab, to evaluate their effectiveness for stomach cancer that cannot be surgically removed or has spread. Some participants will receive these drugs with chemotherapy, while others will receive a different combination. The trial seeks individuals with a confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma who have either not received prior treatment or whose cancer progressed after initial therapy. Participants should have a specific tumor profile identified through a biopsy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that DKN-01 yields promising results in shrinking tumors in some gastric cancer patients. Previous studies have combined DKN-01 with other treatments, though specific safety details from these studies are not provided here. The treatment has received an FDA fast track designation, indicating some confidence in its safety.

Tislelizumab has FDA approval for some cancer patients. In one study, serious side effects occurred in about 54% of patients when combined with chemotherapy. Common side effects included higher blood sugar and lower levels of certain blood cells. While effective, it also presents significant side effects to consider.

Both DKN-01 and tislelizumab are under study in this trial. Since this trial is in a later phase, initial safety checks have already been completed. Participants should discuss potential risks and benefits with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about DKN-01 and tislelizumab for stomach cancer because they bring a fresh approach compared to traditional treatments like chemotherapy alone. Unlike standard options, DKN-01 targets the Dickkopf-1 (DKK1) protein, which is often overexpressed in cancer cells and can promote tumor growth. This makes it a promising candidate for disrupting cancer progression. Tislelizumab, on the other hand, is a PD-1 inhibitor that helps the immune system recognize and attack cancer cells. Together, these treatments offer a dual-action strategy: directly targeting cancer cells and boosting the body's immune response, potentially leading to improved outcomes for patients.

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

This trial will evaluate the effectiveness of using DKN-01 with tislelizumab for treating stomach cancer. Studies have shown that DKN-01 targets DKK1, a protein linked to lower survival rates in stomach cancer, and has demonstrated significant tumor reduction. Participants in this trial will receive different dosages of DKN-01 combined with tislelizumab. These drugs, when combined, help the immune system fight cancer, leading to longer periods without cancer progression and improved overall survival. Early tests have shown this combination to be promising compared to some standard treatments, suggesting it could be a viable option for patients with advanced stomach cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Cynthia Sirard, MD

Principal Investigator

Chief Medical Officer

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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; ±Human Epidermal growth factor Receptor 2 \[HER2\] therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.

Group IV: Part A First Line Treatment Experimental Treatment 4 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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.00410

DKN-01 in Combination With Tislelizumab and ... The outcomes of anti–PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12246393/

DKN-01 and tislelizumab as second-line therapy in DKK1 ... Increased DKK1 expression in gastric cancer is associated with shorter survival. DKN-01 (Leap Therapeutics, Inc.) is a humanized IgG4 monoclonal ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04363801

NCT04363801 | A Study of DKN-01 in Combination With ... Part A and B are designed to evaluate safety, tolerability, and efficacy of the combination therapy of intravenous (IV) DKN-01 and tislelizumab ± CAPOX in G/GEJ ...

4. asco.org asco.org/abstracts-presentations/ABSTRACT403342

A phase 2 study (DisTinGuish) of DKN-01 in combination ... 1L treatment of advanced GEA patients with DKN-01 in combination with tislelizumab and CAPOX resulted in a prolongation of PFS and OS compared with the modern ...

5. leaptx.com leaptx.com/programs/gastric-cancer/

Gastric Cancer - Leap Therapeutics, Inc. Leap Therapeutics' DKN-01 has shown significant tumor reduction in preclinical models and clinical trials for Gastric Cancer patients with DKK1 tumors.

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/01/NCT04363801/Prot_000.pdf

Protocol Title: A Phase 2, Multicenter, Open-Label Study of DKN- ... GLOBOCAN 2018 data, gastric adenocarcinoma is the fifth most common neoplasm and the ... DKN-01 (formerly known as LY2812176) is a humanized monoclonal antibody ( ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9398109/

Safety, Efficacy, and Biomarker Results from a Phase Ib ... We assessed safety and clinical utility of DKN-01 (a novel DKK1-neutralizing IgG4 antibody) combined with pembrolizumab and retrospectively determined DKK1 ...

8. leaptx.com leaptx.com/science/dkn-01/

Sirexatamab (DKN-01) - Leap Therapeutics, Inc. DKN-01 binds and removes free DKK1 from the TME: Reduces cell proliferation, Blocks signaling through CKAP4 and PI3K to downregulate Akt, Suppresses MDSC cells.

9. targetedonc.com targetedonc.com/view/study-of-dkn-01-in-unresectable-locally-advanced-or-metastatic-gastric-gej-cancer-continues-to-part-c

Study of DKN-01 in Unresectable Locally Advanced or ... Also, DKN-01 in combination tislelizumab has an FDA fast track designation for the treatment of gastric/GEJ adenocarcinoma in patients whose ...