NCT05480306已完成2 期
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)
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 188
- 试验地点
- 37
- 主要终点
- Progression Free Survival (PFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients meeting all of the following criteria will be considered eligible for study entry:
- •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.
- •Able to provide written informed consent for any study specific procedures.
- •One or more tumors measurable on radiographic imaging as defined by RECIST 1.1
- •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, renal, hematologic, and coagulation function
- •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
排除标准
- •Patients meeting any of the following criteria are not eligible for study entry:
- •Diagnosis of Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAF V600E mutation positive colorectal cancer.
- •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.
- •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.
- •Prior radiation therapy within 14 days prior to first dose of study drug.
- •Active leptomeningeal disease or uncontrolled brain metastases.
- •Any active cancer ≤ 2 years before first dose of study drug with the exception of cancer for this study.
- •New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
- •Fridericia-corrected QT interval (QTcF) > 470 msec (female) or history of congenital long QT syndrome.
- •Active, uncontrolled bacterial, viral, or fungal infections, within 14 days of study entry requiring systemic therapy.
- •Serious nonmalignant disease
- •Pregnant or nursing.
- •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.
- •Known osteoblastic bony metastasis.
- •Major surgery 28 days prior to study entry.
- •Prior radiation therapy within 14 days prior to study entry.
- •Significant allergy to a pharmaceutical therapy that, in the opinion of the Investigator, poses an increased risk to the patient.
- •Active substance abuse.
- •Known dihydropyrimidine dehydrogenase deficiency.
- •Administration of a live vaccine within 28 days before first dose of study drug
研究组 & 干预措施
Treatment
Experimental
DKN-01 + FOLFIRI or FOLFOX + bevacizumab
干预措施: DKN-01 (Drug)
Treatment
Experimental
DKN-01 + FOLFIRI or FOLFOX + bevacizumab
干预措施: FOLFIRI (Drug)
Treatment
Experimental
DKN-01 + FOLFIRI or FOLFOX + bevacizumab
干预措施: Bevacizumab (Drug)
Treatment
Experimental
DKN-01 + FOLFIRI or FOLFOX + bevacizumab
干预措施: FOLFOX (Drug)
Control
Active Comparator
FOLFIRI or FOLFOX + bevacizumab
干预措施: FOLFIRI (Drug)
Control
Active Comparator
FOLFIRI or FOLFOX + bevacizumab
干预措施: Bevacizumab (Drug)
Control
Active Comparator
FOLFIRI or FOLFOX + bevacizumab
干预措施: FOLFOX (Drug)
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: approximately 6 months
PFS, as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC.
次要结局
- Incidence of ≥Grade 3 related treatment-related adverse events (TRAEs).(approximately 6 months)
- Objective Response Rate (ORR)(approximately 6 months)
- Overall Survival (OS)(approximately 6 months)
- Duration of Response (DoR)(approximately 6 months)
研究者
研究点 (37)
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相关资讯
Leap Therapeutics Publishes DeFianCe Study Results: Plasma DKK1 Emerges as Predictive Biomarker for Sirexatamab Benefit in Second-Line Colorectal Cancer- The randomized Phase 2 DeFianCe study demonstrated that baseline plasma DKK1 levels predict deepening benefit from sirexatamab when added to bevacizumab and chemotherapy in second-line metastatic colorectal cancer patients.
- In DKK1-high patients above the median, sirexatamab improved median PFS to 9.0 months versus 7.1 months (HR 0.61; p=0.0255) and median OS was not reached versus 14.4 months (HR 0.42; p=0.0118).
- Among upper-quartile DKK1-high patients, the OS hazard ratio was 0.17 (p<0.001), with median OS not reached versus 9.5 months, while ORR reached 44.0% compared with 15.8% in the control arm.
- The findings, published in Clinical Cancer Research, provide the scientific foundation for a biomarker-selected Phase 3 registrational trial, with the FDA having granted Fast Track designation in May 2026.last monthLeap Therapeutics Reaches FDA Alignment on Phase 3 Trial for Sirexatamab in DKK1-High Metastatic Colorectal Cancer- Leap Therapeutics reached FDA alignment on a registrational Phase 3 trial of sirexatamab in DKK1-high, second-line metastatic colorectal cancer (mCRC), with objective response rate supporting accelerated approval and overall survival supporting full approval.
- The randomized Phase 2 DeFianCe study, published in Clinical Cancer Research, showed sirexatamab's benefit increases with rising baseline plasma DKK1 levels, defining DKK1-high mCRC as a biologically distinct population with high unmet need.
- Sirexatamab received FDA Fast Track designation in May 2026 for DKK1-high mCRC patients whose disease has progressed following one prior systemic therapy.
- Leap Therapeutics has initiated a strategic process to advance sirexatamab, considering options including an independent spin-out or a partnership with a pharmaceutical or biotechnology company.last monthLeap Therapeutics to Present Final DeFianCe Phase 2 Results for Sirexatamab in Advanced Colorectal Cancer at ESMO 2025- Leap Therapeutics will present final clinical results from the DeFianCe Phase 2 study evaluating sirexatamab (DKN-01) plus bevacizumab and chemotherapy versus standard care in advanced microsatellite stable colorectal cancer.
- The randomized trial tested sirexatamab, an anti-DKK1 monoclonal antibody, as second-line therapy in patients who received one prior systemic treatment for advanced disease.
- Results will be presented at the European Society for Medical Oncology Congress 2025 in Berlin on October 19, highlighting potential advances in colorectal cancer treatment.11 months agoSirexatamab Shows Promise in Colorectal Cancer, Fails to Meet Endpoints in Gastric Cancer- Leap Therapeutics' DeFianCe study showed a 35% objective response rate (ORR) in second-line colorectal cancer (CRC) patients treated with sirexatamab, bevacizumab, and chemotherapy.
- DKK1 levels were highly correlated with clinical activity in CRC patients, suggesting sirexatamab's mechanism is effective in this biomarker-defined population.
- The DisTinGuish study in gastric cancer did not meet its primary endpoints, leading Leap to discontinue Phase 3 development in this indication.
- Leap plans to initiate a Phase 3 registrational study for sirexatamab in second-line CRC, focusing on biomarker-selected populations.last yearLeap Therapeutics Announces Enrollment Completion in Phase 2 DeFianCe Study and FL-501 Development- Leap Therapeutics completed enrollment in Part B of the Phase 2 DeFianCe study, evaluating DKN-01 with bevacizumab and chemotherapy for second-line advanced colorectal cancer, with data expected mid-2025.
- Patient follow-up is ongoing in Part C of the Phase 2 DisTinGuish study, assessing DKN-01 with tislelizumab and chemotherapy in first-line GEJ and gastric cancer, with data anticipated late 2024 or early 2025.
- Leap Therapeutics is advancing FL-501, a monoclonal antibody targeting GDF-15, into development based on promising preclinical data for treating cachexia and other GDF-15-driven diseases.
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