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)

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.

Objective
Primary Objective - To assess whether the addition of DKN-01 to the combination of FOLFIRI/FOLFOX and bevacizumab improves PFS according to RECIST v1.1 as assessed by the Investigator in patients with advanced colorectal cancer compared to SOC (FOLFIRI/FOLFOX and bevacizumab).

Secondary Objectives -
To estimate the objective response rate (ORR) according to the RECIST v1.1 as assessed by the Investigator, the duration of response (DoR) and overall survival (OS) in advanced CRC patients treated with DKN-01 in combination with FOLFIRI/FOLFOX and bevacizumab compared to SOC as a second-line therapy.
To characterize the frequency of toxicity ?Grade 3 treatment-related adverse events (TRAE) associated with each of the treatment arms.

Treatment Drug: DKN-01
Drug: FOLFIRI
Drug: Bevacizumab
Drug: FOLFOX

Key Eligibility 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
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

Applicable Disease Sites
Colon and Rectum

Participating Institutions
UW Health University Hospital