Clinical trial NCT05480306: Phase 2 Study of DKN-01 in Colorectal Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Colorectal Cancer
Colorectal Adenocarcinoma
Colo-rectal Cancer
Colorectal Cancer Metastatic
Keywords: DKK1
colorectal cancer
DKN-01
Lead sponsor: Leap Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2022-07-29
Enrollment: 188
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: approximately 6 months
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: approximately 6 months
measure: Duration of Response (DoR)
timeFrame: approximately 6 months
measure: Overall Survival (OS)
timeFrame: approximately 6 months
measure: Incidence of ≥Grade 3 related treatment-related adverse events (TRAEs).
timeFrame: approximately 6 months
Other outcomes:
measure: Duration of Complete Response (DoCR)
timeFrame: approximately 6 months
measure: Duration of clinical benefit (DoCB)
timeFrame: approximately 6 months
measure: Durable clinical benefit (DCB)
timeFrame: approximately 6 months
measure: Disease control rate (DCR)
timeFrame: approximately 6 months
measure: Time to response (TTR)
timeFrame: approximately 6 months
measure: Exposure-response relationships for DKN-01 as data permit.
timeFrame: approximately 6 months
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Cape Coral
country: United States
facility: Florida Cancer Specialists & Research Institute (FCS)
state: Florida
city: Fleming Island
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Gainesville
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Wellington
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Baton Rouge
country: United States
facility: Hematology Oncology Clinic
state: Louisiana
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Springfield
country: United States
facility: Oncology Hematology Associates - Springfield
state: Missouri
city: Lake Success
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Cornell University
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center - New York
state: New York
city: White Plains
country: United States
facility: White Plains Hospital
state: New York
city: Asheville
country: United States
facility: Messino Cancer Centers
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Faris
state: South Carolina
city: Sioux Falls
country: United States
facility: Sanford Cancer Center
state: South Dakota
city: Chattanooga
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Tacoma
country: United States
facility: MultiCare Tacoma General Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf (UKE) - Universitaeres Cancer Center Hamburg (UCCH)
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg (UKHD) - Nationales Centrum fuer Tumorerkrankungen Heidelberg (NCT)
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen - Klinik fuer Innere Medizin III
city: Magdeburg
country: Germany
facility: Gemeinschaftspraxis fuer Haematologie und Onkologie - Magdeburg
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
city: Busan
country: Korea, Republic of
facility: Dong-A University Medical Center
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: CHA University - Bundang CHA General Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea - St. Vincent's Hospital
Study officials:
affiliation: Leap Therapeutics, Inc.
name: Cynthia Sirard, MD
role: STUDY_DIRECTOR
References: