Phase 2 Study of DKN-01 in Colorectal Cancer

Colorectal Cancer Clinical Trial

— DeFianCe  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05480306
• Other study ID #: DEK-DKK1-P207
• Status: Recruiting
• Phase: Phase 2
• Start date: August 30, 2022
• Est. completion date: October 31, 2025

Study information

• Verified date: June 2024
• Source: Leap Therapeutics, Inc.
• Contact: Cynthia Sirard, MD
• Phone: (617) 714-0357
• Email: csirard[@]leaptx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: October 31, 2025
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colo-rectal Cancer
• Colorectal Adenocarcinoma
• Colorectal Cancer
• Colorectal Cancer Metastatic
• Colorectal Neoplasms

Intervention

Drug:
• DKN-01
30 minute IV infusion (400mg) every two weeks with an additional loading dose in the first cycle of treatment
• FOLFIRI
90-min IV infusion of irinotecan, leucovorin, and fluorouracil followed by a continuous 46-hour infusion of fluorouracil every two weeks
• Bevacizumab
90-min IV infusion (5mg)
• FOLFOX
2 hour IV infusion of oxaliplatin, folinic acid, and fluorouracil followed by a continuous 46-hour infusion of fluorouracil every two weeks

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Leap Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Germany,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Duration of Complete Response (DoCR)	DoCR using RECIST v1.1	approximately 6 months
Other	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
Other	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
Other	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
Other	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
Other	Exposure-response relationships for DKN-01 as data permit.		approximately 6 months
Primary	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	Objective Response Rate (ORR)	ORR, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC	approximately 6 months
Secondary	Duration of Response (DoR)	DoR, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC	approximately 6 months
Secondary	Overall Survival (OS)	OS with DKN-01 plus SOC versus SOC	approximately 6 months
Secondary	Incidence of =Grade 3 related treatment-related adverse events (TRAEs).		approximately 6 months