DKN-01 + Pembrolizumab for Endometrial Cancer

Overseen By Pamela Soliman, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Uterine sarcomas, Autoimmune disease, 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: 1

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining two drugs, DKN-01 (a DKK1-neutralizing monoclonal antibody) and pembrolizumab, can help manage advanced or recurring endometrial cancer. Endometrial cancer affects the lining of the uterus and becomes challenging to treat when it returns or spreads. The trial includes two groups: one receiving DKN-01 and the other receiving pembrolizumab, both administered intravenously. Women diagnosed with advanced or recurrent endometrial cancer who have not previously received certain types of immunotherapy might be suitable candidates for this study. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking all other anti-tumor therapies at least four weeks before starting the trial treatment. If you are on hormonal agents, you will need a 10-day break from them before starting the trial.

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

Research has shown that DKN-01, a type of antibody, has been tested in other studies. These studies suggest it can work well with some chemotherapy treatments. Although detailed safety information remains limited, its testing in humans indicates promise in earlier safety checks.

Pembrolizumab, already approved for treating other cancers, has maintained a consistent safety record. Recent studies have revealed no new or unexpected side effects. In trials with patients who have advanced endometrial cancer, pembrolizumab was generally well-tolerated.

The current study uses both treatments together. While specific safety data for this combination is not yet available, each treatment has demonstrated a reasonable safety record individually. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because DKN-01 and Pembrolizumab offer a novel approach to treating endometrial cancer. Most current treatments focus on hormonal therapies or chemotherapy. DKN-01 stands out as it targets a specific protein involved in cancer growth, potentially stopping the cancer cells more effectively. Pembrolizumab, on the other hand, is an immunotherapy that helps the body's immune system recognize and attack cancer cells. This combination could enhance the effectiveness of the treatment by simultaneously blocking tumor growth and boosting the immune response.

What evidence suggests that the combination of DKN-01 and pembrolizumab could be effective for endometrial cancer?

Research has shown that DKN-01, which participants in this trial may receive, may help treat endometrial cancer, particularly in patients with high levels of a protein called DKK1. In other studies, patients with certain cancers experienced significant tumor shrinkage, with some achieving complete responses lasting over two years. Pembrolizumab, another treatment option in this trial, reduced tumors in about 46% of patients with advanced endometrial cancer and helped them live longer without their cancer worsening. These findings suggest that combining DKN-01 and pembrolizumab could effectively manage advanced or recurring endometrial cancer. ^{1 5 6 7 8}

Who Is on the Research Team?

Pamela T. Soliman

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for women over 18 with advanced or recurrent endometrioid endometrial cancer that can't be cured by surgery or radiation. Participants may have had up to two prior treatments but not with anti-PD-1/L1 mAbs. They must have measurable disease, be in fair health (ECOG 0-2), and not pregnant or breastfeeding. Exclusions include certain other cancers, recent therapies, vaccines, surgeries, active infections, severe hypersensitivities, autoimmune diseases requiring treatment within the past two years, CNS metastases, and significant heart or gastrointestinal conditions.

Inclusion Criteria

I have not been treated with or worsened after anti-PD-1/L1 therapy.

Women of childbearing potential (WoCBP) must be permanently or surgically sterilized or are postmenopausal for greater than 12 months. If uncertain of amenorrhea for 12 months, a pregnancy test will be done to confirm pregnancy status. If ovaries are present and were not previously menopausal at the time of hysterectomy, should have a serum estradiol <10 pm/mL to confirm ovarian senescence

Adequate hematological organ function laboratory values are defined below: ANC ≥1500/µL, Platelets ≥100 000/µL, Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

Exclusion Criteria

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator

I have an autoimmune disease treated with medication in the last 2 years.

I have not received a live vaccine in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive DKN-01 and pembrolizumab by vein. DKN-01 is administered on Day 1 and Day 15 of Cycle 1, and pembrolizumab is administered on Day 1 of each cycle for up to 24 months.

24 months

Day 1 and Day 15 of Cycle 1, then Day 1 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• DKN-01
• Pembrolizumab

Trial Overview The study tests if DKN-01 (a DKK1 inhibitor) combined with pembrolizumab controls advanced/recurrent endometrial cancer better than current options. It's a Phase 2 trial where participants receive both drugs to see how effective this combination is against their cancer.

How Is the Trial Designed?

Group I: Pembrolizumab Experimental Treatment 2 Interventions

Participants will receive pembrolizumab by vein over about 30 minutes on Day 1 of each cycle for up to 24 months.

Group II: DKN-01 Experimental Treatment 2 Interventions

Participants will receive DKN-01 by vein over about 30 minutes to 2 hours on Day 1 of each cycle, as well ason Day 15 of Cycle 1.

DKN-01 is already approved in United States for the following indications:

Approved in United States as DKN-01 for:

• None approved; Orphan Drug Designation for gastric and gastroesophageal junction cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Leap Therapeutics, Inc.

Industry Sponsor

Trials

16

Recruited

1,100+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Pembrolizumab, an immune checkpoint inhibitor, has been approved for treating relapsed MSI-H endometrial cancer after chemotherapy, showing promise in restoring anti-tumor immunity by blocking PD-1 interactions.

Despite encouraging response rates in MSI-H patients, over 50% do not respond to pembrolizumab, highlighting the need for better understanding of MSI status and identifying specific patient populations that may benefit from treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma. Turinetto, M., Lombardo, V., Pisano, C., et al.[2022]

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

The TROPION-Lung08 phase III study is investigating the combination of datopotamab deruxtecan (Dato-DXd) and pembrolizumab as a first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) who have high PD-L1 expression and no actionable genomic alterations, aiming to improve long-term disease control compared to pembrolizumab alone.

Primary endpoints of the study include progression-free survival and overall survival, with secondary endpoints assessing response rates and safety, indicating a comprehensive evaluation of the new treatment's efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROPION-Lung08: phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC. Levy, BP., Felip, E., Reck, M., et al.[2023]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In the KEYNOTE-158 study, pembrolizumab showed a 48% objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, indicating significant antitumor activity.

The treatment was associated with manageable safety, with 76% of patients experiencing treatment-related adverse events, but no fatal events reported, highlighting its potential as a viable option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2023]

Pembrolizumab, a monoclonal antibody targeting PD-1, showed significant efficacy in treating a 79-year-old patient with advanced squamous cell lung cancer, leading to a complete response after just 3 cycles of treatment.

However, the patient developed acute myelomonocytic leukemia after starting pembrolizumab, highlighting a potential safety concern that warrants further investigation into the drug's effects on blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report. Kim, HB., Park, SG., Hong, R., et al.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37001446/

DKK1 is a predictive biomarker for response to DKN-01 Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 ...

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

Leap Therapeutics Reports Positive Updated Data from ... Updated data confirms statistically significant 32% higher ORR and 3.5 month longer PFS in second-line CRC patients with high DKK1 levels ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05761951

NCT05761951 | Phase 2 Study Evaluating the Efficacy of ... To learn if the combination of DKN-01 and pembrolizumab can help to control advanced or recurrent endometrial cancer. Detailed Description. Primary Objective ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0090825823001488

DKK1 is a predictive biomarker for response to DKN-01 DKN-01 monotherapy shows promising objective response, disease control in high tumoral DKK1 recurrent endometrial cancer.

5. investors.leaptx.com investors.leaptx.com/news-releases/news-release-details/leap-therapeutics-presents-dkn-01-clinical-data-society

Leap Therapeutics Presents DKN-01 Clinical Data at the ... DKN-01 demonstrated objective responses, including a monotherapy complete response continuing now for over 2 and a half years, and durable tumor reductions.

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- ... Our preclinical and clinical data suggest that a DKK1 neutralizing antibody, DKN-01, is able to effectively synergize with certain chemotherapeutics and ...

7. speedbiosystems.com speedbiosystems.com/product/DMS1060/anti-human-dkk-1-monoclonal-antibody-sirexatamab-biosimilar-dkn-01-ly-2812176

Anti-human DKK1 monoclonal antibody, sirexatamab ... This monoclonal antibody is part of a collection of biosimilar antibodies in reference to those approved or in clinical investigation.

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

News Release - Investors - Leap Therapeutics Leap's most advanced clinical candidate, sirexatamab (DKN-01), is a humanized monoclonal antibody targeting the Dickkopf-1 ( DKK1 ) protein.