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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05480306
Recruitment Status : Recruiting
First Posted : July 29, 2022
Last Update Posted : January 26, 2023
Sponsor:
Information provided by (Responsible Party):
Leap Therapeutics, Inc.

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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Colorectal Adenocarcinoma Colo-rectal Cancer Colorectal Cancer Metastatic Drug: DKN-01 Drug: FOLFIRI Drug: Bevacizumab Drug: FOLFOX Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : August 30, 2022
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : August 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

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 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

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. Overall Survival (OS) [ Time Frame: approximately 6 months ]
    OS with DKN-01 plus SOC versus SOC

  4. Incidence of ≥Grade 3 related treatment-related adverse events (TRAEs). [ Time Frame: approximately 6 months ]

Other Outcome Measures:
  1. Duration of Complete Response (DoCR) [ Time Frame: approximately 6 months ]
    DoCR using RECIST v1.1

  2. 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

  3. 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."

  4. 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.

  5. 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.

  6. Exposure-response relationships for DKN-01 as data permit. [ Time Frame: approximately 6 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 6 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05480306


Contacts
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Contact: Cynthia Sirard, MD (617) 714-0357 csirard@leaptx.com
Contact: Elizabeth Parker eparker@leaptx.com

Locations
Show Show 44 study locations
Sponsors and Collaborators
Leap Therapeutics, Inc.
Investigators
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Study Director: Cynthia Sirard, MD Leap Therapeutics, Inc.
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Responsible Party: Leap Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05480306    
Other Study ID Numbers: DEK-DKK1-P207
First Posted: July 29, 2022    Key Record Dates
Last Update Posted: January 26, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Leap Therapeutics, Inc.:
DKK1
colorectal cancer
DKN-01
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors