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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)
EU CTIS ID: 2022-501465-40-00
What this study is testing
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 all patients with advanced colorectal cancer and in patients with left sided advanced colorectal cancer compared to standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab].
- Therapeutic exploratory (Phase II)
A plain-language read of the study's public EU CTIS listing. The study team confirms the details.
Who can take part
You may be able to join if
- 1. 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.
- 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
- 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
You likely can't join if
- Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAF V600E mutation positive colorectal cancer
- 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.
See the full eligibility criteria
Who can join
- 1. 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.
- 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
- 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
What rules you out
- Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAF V600E mutation positive colorectal cancer
- 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
- 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).
- 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
- 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
- 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
- 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
The study team makes the final eligibility decision.
Where it's taking place
- United States
- Korea, Republic of
Questions & answers
Do participants get paid in this trial?
This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.
Is it free to join, and do I need insurance?
Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.
How long does this study last?
The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.
Who can join this trial?
This study is enrolling all sexes, 65+ years, 18-64 years. The study team makes the final eligibility decision.
Where is this trial taking place?
Study sites include United States; Korea, Republic of. Enter your location above to see the nearest site and check your eligibility.
Explore other conditions
BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from EU CTIS; the study team decides eligibility.