DeFianCe: Assessing DKN-01 Plus FOLFIRI/FOLFOX and Bevacizumab in Advanced CRC

John Strickler, MD

The phase 2 DeFianCe study (NCT05480306) is evaluating DKN-01 in combination with standard of care bevacizumab (Avastin) and chemotherapy in the second-line for patients with advanced colorectal cancer (CRC).

DKN-01 is a humanized monoclonal antibody which binds to and blocks the activity of the Dickkopf-1 (DKK1) protein. DKK1 is important as it promotes tumor proliferation, metastasis, angiogenesis, and mediates an immunosuppressive tumor microenvironment.

DeFianCe is a randomized, open-label, multicenter, 2-part study where investigators are evaluating DKN-01 in combination with bevacizumab and chemotherapy in patients with advanced CRC who have received 1 prior systemic therapy.

Approximately 150 advanced patients with microsatellite stable, BRAF wild-type mCRC will be enrolled in parts A and B of the study. Part A is the safety run-in portion of the trial evaluating the combination of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab in at least 20 safety evaluable patients. Then in part B, around 130 patients will be randomized in a 1:1 ratio and given either the experimental or control arm.

In the experimental arm, patients will be administered DKN-01 via 30-minute intravenous (IV) infusion of 400 mg every 2 weeks with an additional loading dose in the first cycle of treatment and bevacizumab at 5 mg by IV infusion every 2 weeks. Additionally, patients will receive one of two chemotherapy regimens at the treating physician’s discretion which includes either an IV infusion of irinotecan, leucovorin, and fluorouracil (FOLFIRI) followed by a continuous 46-hour infusion of fluorouracil every 2 weeks, or an IV infusion of oxaliplatin, folinic acid, and fluorouracil (FOLFOX) and a continuous 46-hour infusion of fluorouracil every 2 weeks. In the control arm, patients will be given a matching treatment regimen but without DKN-01.

The trial enrolled its first patient in October 2022 and is actively recruiting more. The planned study completion date is August 2024.

In an interview with Targeted Oncology^TM, John Strickler, MD, associate professor of medicine at Duke University Medical Center, discussed the background and goals of the DeFianCe study in the colorectal cancer space.

Targeted Oncology: What outcomes are typically shown with standard-of-care second-line chemotherapy combinations in patients with advanced or metastatic colorectal cancer?

Strickler: Currently, in the second-line setting, we have cytotoxic chemotherapy as our standard-of-care. That generally has a low response rate, sometimes in the single digits. Generally it controls the disease for around 6 months. In the second-line setting, we think about cytotoxic chemotherapy as a way to control the disease, not necessarily shrink it. Our goal is to maintain that disease control while still trying to manage a decent quality-of-life for patients.

What disease characteristics contribute to poor outcomes with standard-of-care treatment?

Generally, standard-of-care treatment, which consists of chemotherapy combinations, works best in the frontline setting, particularly in the first 4 months that we give it. Then after that point, we see general stabilization of the disease. That creates a challenge because these combinations of chemotherapy can be difficult for patients to tolerate, particularly as we get deeper into treatment and that response has been maximized. It becomes a challenge to control disease while at the same time supporting a good quality-of-life.

What are some novel targets in this space that can address some of these factors?

Well, there are a number of exciting developments in the area of colorectal cancer. DKK1 is a protein that is overexpressed in many cancers, leading to poor prognosis for patients. It has a significant effect on the tumor microenvironment, promoting the development of cancers through suppression of anti-tumor immune response. We know this is an important target for many gastrointestinal cancers, including upper GI cancers and colorectal cancer.DKN-01 is an investigational drug that targets DKK1. The DeFianCe trial is investigating DKN-01 in combination with standard therapy.

Homing in on DKK1, what do we know about this protein from preclinical research?

What we know from preclinical research is that this is an important protein for the growth and development of solid tumors. It may have particular relevance for gastrointestinal cancers, like gastroesophageal cancers and colorectal cancer. High DKK1 expression has been associated with resistance to standard of care therapies.

DKN-01 is a drug that is able to bind to and reverse the pro-tumorigenic effects of DKK1. DKN-01 slows tumor growth, blocks immunosuppressive cells in the tumor microenvironment, reduces blood vessel growth near the tumor, and activates certain types of anti-tumor immune cells.

What is being evaluated in the phase 2 DeFianCe study?

The DeFianCe trial includes 2 parts. Part A is a safety lead-in in which all patients receive DKN-01 with either FOLFOX or FOLFIRI. Then at the conclusion of the safety run-in, a decision is made to then expand the trial. In the expanded portion of the trial, 130 patients are randomized 1:1 to either the standard-of-care, which is chemotherapy and bevacizumab, or the experimental arm, which is chemotherapy, bevacizumab, and DKN-01.

Currently, the study is in its safety run-in and we're looking forward to getting that first signal to ensure that safety is confirmed. Then we'll hopefully expand the study to the randomized portion. Based on the safety, tolerability, and the activity seen in that part A portion, the decision will be made on whether to expand the study into its randomized part B.

What is important to note about this trial?

I think this is an exciting trial. It's one that appears to be highly relevant to patients with colorectal cancer. Already, we've seen promising safety and efficacy data in patients with gastroesophageal cancers. I would encourage patients and their families to reach out to active clinical trial sites and find a trial site closest to them. This is something that will be invaluable, hopefully for the patients participating, but also for the general cancer research community. We need to find more treatments that help people with metastatic colorectal cancer live longer and live better. That's the goal of this trial.

What unmet needs still exist in the colorectal cancer space?

There are a number of unmet needs. Currently, we're still reliant on cytotoxic chemotherapy. We need to develop more targeted therapies that are both well-tolerated and give people a longer life, without the need for cytotoxic chemotherapy.

REFERENCE:

Wainberg ZA, Boccia RV, Strickler J, et al. 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). J Clin Oncol. 2023 Feb; 41 (suppl 4) TPS275-TPS275. doi:10.1200/JCO.2023.41