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

• ClinicalTrials.gov Identifier: NCT05480306
• Recruitment Status: Recruiting
• First Posted: July 29, 2022
• Last Update Posted: April 23, 2024
• Sponsor: Leap Therapeutics, Inc.
• Information provided by (Responsible Party): Leap Therapeutics, Inc.

Tracking Information

• First Submitted Date: July 21, 2022
• First Posted Date: July 29, 2022
• Last Update Posted Date: April 23, 2024
• Actual Study Start Date: August 30, 2022
• Estimated Primary Completion Date: December 15, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 28, 2022)

Progression Free Survival (PFS) [ Time Frame: approximately 6 months ]

PFS, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC.

Original Primary Outcome Measures (submitted: July 27, 2022)

PFS [ Time Frame: approximately 6 months ]

PFS, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC.

Current Secondary Outcome Measures (submitted: July 27, 2022)

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

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 27, 2022)

• Duration of Complete Response (DoCR) [ Time Frame: approximately 6 months ]
  DoCR using RECIST v1.1
• Duration of clinical benefit (DoCB) [ Time Frame: approximately 6 months ]
  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
• Durable clinical benefit (DCB) [ Time Frame: approximately 6 months ]
  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."
• Disease control rate (DCR) [ Time Frame: approximately 6 months ]
  DCR (i.e., CR+PR+SD at ≥8 weeks), as assessed by the Investigator using RECIST v1.1.
• Time to response (TTR) [ Time Frame: approximately 6 months ]
  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.
• Exposure-response relationships for DKN-01 as data permit. [ Time Frame: approximately 6 months ]

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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)
• 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 150 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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: DKN-01
  30 minute IV infusion (400mg) every two weeks with an additional loading dose in the first cycle of treatment
  Other Name: 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

Study Arms

• Experimental: Treatment
  DKN-01 + FOLFIRI or FOLFOX + bevacizumab
  Interventions:

  • Drug: DKN-01
  • Drug: FOLFIRI
  • Drug: Bevacizumab
  • Drug: FOLFOX
• Active Comparator: Control
  FOLFIRI or FOLFOX + bevacizumab
  Interventions:

  • Drug: FOLFIRI
  • Drug: Bevacizumab
  • Drug: FOLFOX

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 27, 2022): 150
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 15, 2025
• Estimated Primary Completion Date: December 15, 2025 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cynthia Sirard, MD; (617) 714-0357; csirard@leaptx.com

Contact: Elizabeth Parker; eparker@leaptx.com

• Listed Location Countries: Germany, Korea, Republic of, United States

Administrative Information

• NCT Number: NCT05480306
• Other Study ID Numbers: DEK-DKK1-P207
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Leap Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Leap Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Cynthia Sirard, MD; Leap Therapeutics, Inc.

• PRS Account: Leap Therapeutics, Inc.
• Verification Date: April 2024