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)
- Trial ID
- 2022-501465-40-00
- Protocol
- DEK-DKK1-P207
- Sponsor
- Leap Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized Phase 2 study is to assess whether the addition of **DKN-01** to the combination of FOLFIRI/FOLFOX and **bevacizumab** improves progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by the Investigator in patients with advanced colorectal cancer, including those with left-sided advanced colorectal cancer, compared to the standard of care (SOC) regimen of FOLFIRI/FOLFOX and bevacizumab. This is clinically relevant as improving PFS can potentially lead to better management of advanced colorectal cancer, offering patients a more effective second-line treatment option.
Secondary objectives include:
- Estimating the objective response rate (ORR) according to RECIST v1.1, the duration of response (DoR), and overall survival (OS) in advanced colorectal cancer patients treated with DKN-01 in combination with FOLFIRI/FOLFOX and bevacizumab compared to SOC as a second-line therapy.
- Characterizing the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each of the treatment arms.
Participants
The clinical trial involves a total of **131 participants** diagnosed with **colorectal cancer**, specifically targeting those with advanced stages of the disease. The study population includes both male and female subjects, with an age requirement of **18 years and older** in North America and **19 years and older** in the Republic of Korea. Participants were selected based on a histologically confirmed diagnosis of advanced colorectal adenocarcinoma, with documented disease progression following first-line systemic therapy. The trial includes individuals with a performance status of **ECOG 1 or less**, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have acceptable liver, renal, and hematologic function, and females of childbearing potential, as well as non-sterile males, are required to use highly effective contraception methods. The trial population is inclusive of vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified, but participants must comply with the study's requirements and schedule of assessments.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of adding **DKN-01** to the standard treatment regimen of FOLFIRI/FOLFOX and **bevacizumab** in patients with advanced **colorectal cancer**. The primary objective is to assess progression-free survival (PFS) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The trial is expected to last until September 2025, with recruitment having commenced in January 2023. Participants will be randomly assigned to receive either the investigational treatment or the standard of care (SOC) and will be monitored for various endpoints, including objective response rate (ORR), duration of response (DoR), overall survival (OS), and the incidence of treatment-related adverse events (TRAEs).
The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven advanced colorectal adenocarcinoma, acceptable coagulation, liver, and renal function, and ECOG performance status. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as imaging studies to evaluate tumor response, laboratory tests, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
Participant involvement is anticipated to last up to 12 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or any other medical condition that, in the investigator's opinion, would compromise the participant's safety or the integrity of the study data. The trial is conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **DKN-01**, an experimental medication, which is a humanized IgG4-kappa monoclonal antibody targeting DKK1, also known as **sirexatamab**. This medication is provided in the form of an **injection** and is administered **intravenously**. The maximum daily dose is 400 mg, with a total dose not exceeding 400 mg over a treatment period of up to 12 weeks. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.
**Irinotecan Hydrochloride** is used as a comparator treatment in the study. It is supplied as a **concentrate for solution for infusion** and is administered as a **solution for infusion**. The maximum daily dose is 180 mg/m², with a total dose not exceeding 180 mg/m² over a treatment period of 1 week. This medication is a chemical compound and is not a pediatric formulation.
**Fluorouracil**, marketed as Fluorouracil Hikma 50 mg/ml, is another comparator treatment. It is provided as a **solution for injection** and administered **intravenously**. The maximum daily dose is 1200 mg/m², with a total dose not exceeding 1200 mg/m² over a treatment period of 1 week. This chemical compound is also not a pediatric formulation.
**Calcium Folinate** is included in the study as a supportive treatment. It is available as a **solution for injection** and administered **intravenously**. The maximum daily dose is 400 mg/m², with a total dose not exceeding 400 mg/m² over a treatment period of 2 weeks. This chemical compound is used to mitigate the toxic effects of other chemotherapy agents.
**Oxaliplatin**, provided as a 5 mg/ml concentrate for solution for infusion, is used in the trial. It is administered as a **solution for infusion**. The maximum daily dose is 85 mg/m², with a total dose not exceeding 85 mg/m² over a treatment period of 2 weeks. This chemical compound is part of the standard chemotherapy regimen.
**Bevacizumab**, marketed as Aybintio 25 mg/ml, is used in combination with other treatments. It is provided as a **concentrate for solution for infusion** and administered as an **infusion**. The maximum daily dose is 5 mg/kg, with a total dose not exceeding 5 mg/kg over a treatment period of 2 weeks. This protein-based medication is used to inhibit angiogenesis in cancer treatment.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, as determined by the Investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). This assessment will compare the efficacy of DKN-01 plus standard of care (SOC) versus SOC alone in patients with advanced colorectal cancer, including those with left-sided advanced colorectal cancer. Secondary efficacy endpoints include the **Objective Response Rate (ORR)**, **Duration of Response (DoR)**, and **Overall Survival (OS)**, all evaluated per RECIST v1.1. Additionally, the incidence of treatment-related adverse events of Grade 3 or higher will be monitored.
The trial will involve the administration of DKN-01 in combination with FOLFIRI/FOLFOX and bevacizumab, compared to the administration of FOLFIRI/FOLFOX and bevacizumab alone. The efficacy parameters will be measured at various timepoints throughout the study, with assessments conducted by the Investigator. The trial is designed to provide a comprehensive evaluation of the potential benefits of adding DKN-01 to the existing treatment regimen for advanced colorectal cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically proven diagnosis of advanced colorectal adenocarcinoma (by local laboratory and local clinical guidelines) with documented objective radiographic or symptomatic disease progression following first-line systemic therapy with any fluoropyrimidine-based regimen for advanced disease (except FOLFOXIRI, see exclusion #3). • 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.
- Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
- Age ≥18 years in North America or ≥19 years in the Republic of Korea on the day of signing the informed consent form
- Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1. (A lesion in an area subjected to prior loco-regional therapy, including previous radiotherapy, is not considered measurable unless there has been demonstrated progression in the lesion since the therapy as defined by RECIST v1.1.)
- Sufficient tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred], or archived tissue block specimen).
- ECOG performance status ≤1 within 7 days of first dose of study drug
- Acceptable liver function: a. Total bilirubin ≤1.5 times upper limit of normal (ULN) (if Gilbert’s disease present, then ≤3.0 times ULN is allowed). b. AST and ALT, ≤2.5 times ULN (if liver metastases are present, then ≤5 × ULN is allowed).
- Acceptable renal function: a. Serum creatinine ≤1.5 × ULN or estimated glomerular filtration rate ≥30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration equation
- Acceptable hematologic status (in the Republic of Korea patients must not have required blood transfusion or growth factor support within 14 days before sample collection at screening for the following): a. Absolute neutrophil count (ANC) ≥1.5 × 109/L. b. Platelets ≥100 × 109/L c. Hemoglobin ≥9 g/dL
- Acceptable coagulation status: a. Prothrombin time/activated partial thromboplastin time ≤1.2 × ULN (unless receiving anticoagulation therapy, if receiving anticoagulation therapy, eligibility will be based upon international normalized ratio (INR), see (b) below. b. INR ≤1.5 (unless receiving anticoagulation therapy) If receiving anticoagulant: INR ≤3.0 and no active bleeding, (i.e., no clinically significant bleeding within 14 days prior to first dose of study drugs).
- Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and for at least 6 months after the last dose of study drugs and have a negative urine or serum pregnancy test within 7 days before first dose of study drugs
- Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for at least 6 months after the last dose of study drugs. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. a. A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. b. Males with known “low sperm counts” (consistent with “sub-fertility”) are not to be considered sterile for purposes of this study
Exclusion Criteria
- Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAF V600E mutation positive colorectal cancer
- Any active malignancy ≤2 years before first dose of study drug, with the exception of the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
- Uncontrolled diabetes or >Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥Grade 3 hypoalbuminemia within 14 days before first dose of study drug
- Uncontrolled arterial hypertension defined by blood pressure >150 mmHg systolic and/or 100 mmHg diastolic at rest despite appropriate medical therapy within 28 days before first dose of study drug.
- Proteinuria, as demonstrated by >1.5 gram of protein in a 24-hour urine collection. All patients with ≥2+ protein on dipstick urianalysis at baseline must undergo 24-hr urine collection for protein.
- Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage within 7 days prior to first dose of study drug (the cytological confirmation of any effusion is permitted).
- Clinically significant anorexia (CTCAE ≥Grade 2) within 7 days prior to first dose of study drug.
- Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection within 14 days of first dose of study drug.
- Prior allogeneic stem cell transplantation or organ transplantation
- Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living within 28 days before first dose of study drug. b. Pulmonary embolism within 28 days before first dose of study drug. c. Any history of acute myocardial infarction within 6 months before first dose of study drug. d. Any history of heart failure meeting New York Heart Association Classification III or IV within 6 months before first dose of study drug. e. Any event of ventricular arrhythmia ≥Grade 2 in severity within 6 months before first dose of study drug. f. Any history of cerebrovascular accident, including transient ischemic attack, within 6 months before first dose of study drug. g. Clinically significant peripheral artery disease
- Evidence of bleeding diathesis or significant coagulopathy
- Prior therapy with an anti-DKK1 agent
- Any episode of syncope or seizure within 28 days before first dose of study drug
- Fridericia-corrected QT interval >470 msec (female) or >450 (male), or history of congenital long QT syndrome. Any ECG abnormality that in the opinion of the Investigator would preclude safe participation in the study; patients with pacemakers where QTc is not a reliable measure will require an evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study.
- Known to be human immunodeficiency virus (HIV) positive unless HIV RNA is undetected, have hepatitis B surface antigen, or hepatitis C antibodies unless hepatitis C virus ribonucleic acid (RNA) is undetected/negative
- Serious nonmalignant disease or other circumstance that could compromise protocol objectives or place the patient at risk in the opinion of the Investigator and/or the Sponsor
- History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on magnetic resonance imaging (MRI) scan that are symptomatic and clinically significant. Degenerative changes of the hip joint are not exclusionary. Screening of asymptomatic patients is not required
- Known osteoblastic bony metastasis. Screening of asymptomatic patients without a history of metastatic bony lesions is not required
- Serious psychiatric or medical conditions that could interfere with treatment
- Toxicities (as a result of prior anticancer therapy) that have not recovered to baseline or stabilized, except for AEs not considered a likely safety risk (e.g., alopecia, neuropathy and specific laboratory abnormalities).
- Administration of a live vaccine within 28 days before first dose of study drug. Note: Seasonal vaccines for influenza or COVID-19 vaccines are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed
- Prior therapy with FOLFOXIRI
- Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug, or affect the explanation of drug toxicity or AEs, or result in insufficient or impaired compliance with study conduct
- Women who are pregnant or are breastfeeding
- Concurrent participation in another therapeutic clinical study Note: Concurrent participation in observational or non-interventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow-up period can be enrolled in this study
- Prior therapy with an anti-programmed cell death protein ligand-1 [PD-(L)1] or anti-programmed cell death protein ligand-2 (PD-L2) or any other antibody or drug specifically targeting T-cell co-stimulation or coinhibitory checkpoint pathways in any treatment setting (including adjuvant/neoadjuvant).
- Systemic anti-cancer therapy within 28 days prior to first dose of study drug
- Major surgery within 28 days prior to first dose of study drug
- Treatment with radiation therapy within 14 days prior to first dose of study drug
- Active leptomeningeal disease or uncontrolled brain metastases. Patients with equivocal findings or with confirmed brain metastases are eligible for the study provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment or seizure prophylaxis for ≥4 weeks before first dose of study drug.
- History of gastrointestinal perforation and/or fistulae within 6 months prior to first dose of study drug, clinically significant bleeding from the gastrointestinal tract, or clinically significant bowel obstruction (CTCAE ≥Grade 2) within 28 days before first dose of study drug.
- Known UGT1A1 deficiency
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Jan 2023 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CALCIUM FOLINATE | Other | — | INTRAVENOUS | 400 | 2 | SUB06052MIG |
Fluorouracil Hikma 50 mg/ml Injektionslösung | Other | INJEKTIONSLÖSUNG | INTRAVENOUS | 1200 | 1 | PRD7117395 |
IRINOTECAN HYDROCHLORIDE | Other | — | SOLUTION FOR INFUSION | 180 | 1 | SUB02772MIG |
DKN-01 | Test | INJECTION | INTRAVENOUS | 400 | 12 | PRD9964637 |
Oxaliplatin 5mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 85 | 2 | PRD8279123 |
Aybintio 25 mg/ml concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 5 | 2 | PRD8313460 |