Phase 2 Study of DKN-01 in Colorectal Cancer (DeFianCe)

Randomized Phase 2 Study of DKN-01 Plus FOLFIRI/FOLFOX and Bevacizumab Versus FOLFIRI/FOLFOX and Bevacizumab as Second-line Treatment of Advanced 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 bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as second-line treatment of advanced CRC patients.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Colorectal Cancer Metastatic; Colo-rectal Cancer; Colorectal Adenocarcinoma
• Intervention / Treatment: Drug: DKN-01; Drug: FOLFIRI; Drug: Bevacizumab; Drug: FOLFOX

Detailed Description

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 bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as second-line treatment of advanced CRC patients.

In Parts A and B, approximately 200 evaluable adult advanced CRC patients with measurable disease (RECIST v1.1) who have radiographically progressed during or following 1 line of systemic treatment will be enrolled in the study.

The study consists of a Screening Period, a Treatment Period, a Safety Follow-up Period (SFUP) and a Long-Term Follow-up Period (LTFU). Patients will be followed in the SFUP for approximately 30 days (+7 days) after the last administration of study drug and then enter the LTFU period to be followed for survival and subsequent therapies. Additionally, patients that ended study treatment for a reason unrelated to progressive disease [PD] will also be followed for disease progression in the LTFU period.

• Study Type: Interventional
• Enrollment (Actual): 188
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany
    • Universitaetsklinikum Hamburg-Eppendorf (UKE) - Universitaeres Cancer Center Hamburg (UCCH)
  • Heidelberg, Germany
    • Universitaetsklinikum Heidelberg (UKHD) - Nationales Centrum fuer Tumorerkrankungen Heidelberg (NCT)
  • Heilbronn, Germany
    • SLK-Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen - Klinik fuer Innere Medizin III
  • Magdeburg, Germany
    • Gemeinschaftspraxis fuer Haematologie und Onkologie - Magdeburg
  • Mainz, Germany
    • Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
• Korea, Republic of
  • Busan, Korea, Republic of
    • Dong-A University Medical Center
  • Daegu, Korea, Republic of
    • Kyungpook National University Chilgok Hospital
  • Incheon, Korea, Republic of
    • Inha University Hospital
  • Incheon, Korea, Republic of
    • Gachon University Gil Medical Center
  • Seongnam-si, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seongnam-si, Korea, Republic of
    • CHA University - Bundang CHA General Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Suwon, Korea, Republic of
    • The Catholic University of Korea - St. Vincent's Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • The University of Arizona Cancer Center
  • California
    • Los Angeles, California, United States, 90404
      • UCLA
  • Florida
    • Cape Coral, Florida, United States, 33909
      • Florida Cancer Specialists & Research Institute (FCS)
    • Fleming Island, Florida, United States, 32003
      • Florida Cancer Specialists & Research Institute
    • Gainesville, Florida, United States, 32605
      • Florida Cancer Specialists & Research Institute
    • Miami, Florida, United States, 33176
      • Miami Cancer Institute
    • Wellington, Florida, United States, 33414
      • Florida Cancer Specialists & Research Institute
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Hematology Oncology Clinic
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center for Cancer and Blood Disorders
  • Missouri
    • Springfield, Missouri, United States, 65807
      • Oncology Hematology Associates - Springfield
  • New York
    • Lake Success, New York, United States, 11020
      • Northwell Health
    • New York, New York, United States, 10016
      • New York University
    • New York, New York, United States, 10021
      • Cornell University
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center - New York
    • White Plains, New York, United States, 10601
      • White Plains Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Messino Cancer Centers
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Faris
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Cancer Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Tacoma General Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Adult patients with advanced CRC with measurable disease (RECIST v1.1) who have radiographically progressed during or following one line of systemic treatment will be enrolled in the study.

Inclusion Criteria:

Patients meeting all of the following criteria will be considered eligible for study entry:

1. Disease progression following first-line systemic therapy with any fluoropyrimidine-based regimen for advanced disease (except FOLFOXIRI, see exclusion criteria).

   • Patients may have received prior neoadjuvant or adjuvant therapy which could have included irinotecan or oxaliplatin. If progression has occurred within 12 months from last dose of neoadjuvant or adjuvant treatment, this regimen will be considered as the one line of systemic therapy for advanced disease.

   • If assigned to receive FOLFIRI, patient may have received no prior irinotecan as part of first-line systemic therapy.
   • If assigned to receive FOLFOX, patient may have received no prior oxaliplatin as part of first line systemic therapy.
   • Prior treatment with an anti-VEGF or anti-EGFR therapy is allowed as first-line and/or maintenance systemic therapy.
2. Able to provide written informed consent for any study specific procedures.
3. One or more tumors measurable on radiographic imaging as defined by RECIST 1.1
4. Sufficient tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred], or archived tissue block specimen).
5. ECOG performance status ≤1 within 7 days of first dose of study drug. Acceptable liver, renal, hematologic, and coagulation function
6. Females of childbearing potential and male partners of female patients must agree to use adequate contraception during the study and for 6 months after their last dose of study drug

Exclusion Criteria:

Patients meeting any of the following criteria are not eligible for study entry:

1. Diagnosis of Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAF V600E mutation positive colorectal cancer.
2. Prior therapy with an anti-DKK1, FOLFOXIRI, PD-1, anti-PD-L1, anti-PD-L-2 or any other antibody or drug specifically targeting T-cell co-stimulation or coinhibitory checkpoint.
3. Systemic anti-cancer therapy within 28 days prior to first dose of study drug.
4. Major surgery within 28 days prior to first dose of study drug.
5. Prior radiation therapy within 14 days prior to first dose of study drug.
6. Active leptomeningeal disease or uncontrolled brain metastases.
7. Any active cancer ≤ 2 years before first dose of study drug with the exception of cancer for this study.
8. New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
9. Fridericia-corrected QT interval (QTcF) > 470 msec (female) or history of congenital long QT syndrome.
10. Active, uncontrolled bacterial, viral, or fungal infections, within 14 days of study entry requiring systemic therapy.
11. Serious nonmalignant disease
12. Pregnant or nursing.
13. History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on MRI scan that are symptomatic and clinically significant.
14. Known osteoblastic bony metastasis.
15. Major surgery 28 days prior to study entry.
16. Prior radiation therapy within 14 days prior to study entry.
17. Significant allergy to a pharmaceutical therapy that, in the opinion of the Investigator, poses an increased risk to the patient.
18. Active substance abuse.
19. Known dihydropyrimidine dehydrogenase deficiency.
20. Administration of a live vaccine within 28 days before first dose of study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; DKN-01 + FOLFIRI or FOLFOX + bevacizumab	Drug: DKN-01; 30 minute IV infusion (400mg) every two weeks with an additional loading dose in the first cycle of treatment; Other Names: LY2812176; Drug: FOLFIRI; 90-min IV infusion of irinotecan, leucovorin, and fluorouracil followed by a continuous 46-hour infusion of fluorouracil every two weeks; Drug: Bevacizumab; 90-min IV infusion (5mg); Drug: FOLFOX; 2 hour IV infusion of oxaliplatin, folinic acid, and fluorouracil followed by a continuous 46-hour infusion of fluorouracil every two weeks
Active Comparator: Control; FOLFIRI or FOLFOX + bevacizumab	Drug: FOLFIRI; 90-min IV infusion of irinotecan, leucovorin, and fluorouracil followed by a continuous 46-hour infusion of fluorouracil every two weeks; Drug: Bevacizumab; 90-min IV infusion (5mg); Drug: FOLFOX; 2 hour IV infusion of oxaliplatin, folinic acid, and fluorouracil followed by a continuous 46-hour infusion of fluorouracil every two weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC.	approximately 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC	approximately 6 months
Duration of Response (DoR)	DoR, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC	approximately 6 months
Overall Survival (OS)	OS with DKN-01 plus SOC versus SOC	approximately 6 months
Incidence of ≥Grade 3 related treatment-related adverse events (TRAEs).		approximately 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Complete Response (DoCR)	DoCR using RECIST v1.1	approximately 6 months
Duration of clinical benefit (DoCB)	DoCB as determined using RECIST v1.1, is defined as the time from the date of randomization (or date of registration for Part A patients) to the time of progressive disease or death due to any cause in patients who had a best overall response of complete response (CR), partial response (PR), or stable disease (SD) of ≥8 weeks	approximately 6 months
Durable clinical benefit (DCB)	DCB, defined as DoCB ≥180 days. Patients who have best overall response of PD or those having clinical benefit but DoCB lasting <180 days will be considered as "non-DCB."	approximately 6 months
Disease control rate (DCR)	DCR (i.e., CR+PR+SD at ≥8 weeks), as assessed by the Investigator using RECIST v1.1.	approximately 6 months
Time to response (TTR)	TTR, defined as the time from the date of randomization (or date of registration for Part A patients) to the assessment date of the first instance of an overall response of CR or PR.	approximately 6 months
Exposure-response relationships for DKN-01 as data permit.		approximately 6 months

Collaborators and Investigators

• Sponsor: Leap Therapeutics, Inc.
• Investigators: Study Director: Cynthia Sirard, Leap Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2022
• Primary Completion (Actual): July 10, 2025
• Study Completion (Actual): July 10, 2025

Study Registration Dates

• First Submitted: July 21, 2022
• First Submitted That Met QC Criteria: July 27, 2022
• First Posted (Actual): July 29, 2022

Study Record Updates

• Last Update Posted (Actual): August 3, 2025
• Last Update Submitted That Met QC Criteria: July 30, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: colorectal cancer; DKK1; DKN-01
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: DEK-DKK1-P207

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No