sirexatamab (DKN-01)

P2, N=150, Recruiting, Leap Therapeutics, Inc. | Trial completion date: Aug 2024 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Dec 2025

P2, N=15, Terminated, Massachusetts General Hospital | N=30 --> 15 | Recruiting --> Terminated; Based on a Simon 2-stage design, this study did not meet response criteria to proceed to stage 2.

Other targeted agents, such as bemarituzumab and DKN-01, are under active investigation. As new agents are incorporated into the treatment continuum, the questions of biomarker overlap, tumor heterogeneity, and toxicity management will need to be addressed.

DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

Ongoing efforts to identify novel biomarkers in EGA have led to enhanced subclassification of upper GI cancers. These advances, coupled with the strategic application of targeted therapies and immunotherapy when appropriate, hold promise to further improve patients outcomes.

P2, N=232, Active, not recruiting, Leap Therapeutics, Inc. | Recruiting --> Active, not recruiting

P1/2, N=18, Terminated, NYU Langone Health | Phase classification: P1b/2a --> P1/2

P1/2, N=52, Recruiting, Royal Marsden NHS Foundation Trust | Phase classification: P2 --> P1/2

Elevated DKK1 expression has been shown to correlate with fluorouracil (5FU) resistance in CRC tumors... DeFianCe (NCT05480306) is a Phase 2 randomized, open-label, two-part, multicenter study to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as 2L treatment of advanced MSS CRC patients (pts)...All patients had received prior 5FU-based therapies, 30 pts (91%) with oxaliplatin in combination and 17 pts (52%) had prior bevacizumab... DKN-01 in combination with SOC was well tolerated with promising preliminary activity (ORR 30% and DCR 93%) in the single arm Part A. PFS has not been reached and survival follow up is ongoing. Part B randomized expansion phase has begun and is enrolling an additional 130 pts. Tumoral DKK1 expression and correlation with clinical outcomes will be evaluated as an exploratory efficacy endpoint.

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

P2, N=60, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=232, Recruiting, Leap Therapeutics, Inc. | Phase classification: P2a --> P2 | N=72 --> 232 | Trial completion date: Jun 2023 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Jun 2025

<1 n=13 (27%); 1-<10 n=22 (45%); ≥10 n=14 (29%). 38 pts with genomic profiling: Wnt activating mutations in 12 pts, no MSI-H. 4 pts were IO experienced.

DKK1 promotes tumour immune evasion in iCCA through the recruitment of immune suppressive macrophages. Targeting DKK1 with a neutralizing antibody is effective at reducing tumour growth in vivo. As such, DKK1 targeted and immune modulatory therapies may be an effective strategy in iCCA patients with high DKK1 tumour expression or tolerogenic immune phenotypes.

Conclusions DKN-01 plus atezolizumab has a manageable safety profile with no new safety signals in pts with advanced OGA. DKN-01 600mg plus atezolizumab 840mg q2W was the RP2D taken through to the ongoing expansion phase to confirm efficacy.

P1b/2a, N=18, Active, not recruiting, NYU Langone Health | Recruiting --> Active, not recruiting | N=97 --> 18 | Trial completion date: Dec 2022 --> Aug 2023

P2a, N=72, Recruiting, Leap Therapeutics, Inc. | Trial completion date: May 2022 --> Jun 2023 | Trial primary completion date: Dec 2021 --> Dec 2022

P1b/2a, N=97, Recruiting, NYU Langone Health | Trial completion date: Mar 2021 --> Dec 2022 | Trial primary completion date: Mar 2021 --> Dec 2022

Wnt/β-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy.

P1, N=151, Completed, Leap Therapeutics, Inc. | Active, not recruiting --> Completed

DKN-01 combined with pembrolizumab was well tolerated with no new safety signals. Antitumor activity was enriched in anti-PD-1/PD-L1-naïve GEJ/GC patients whose tumors expressed high DKK1.

DKN-01 is a humanized monoclonal therapeutic antibody that binds DKK1 with high affinity and has demonstrated clinical activity in gastric/gastroesophageal junction (G/GEJ) patients with elevated tumoral expression of DKK1...The DKK1 RNAscope assay in conjunction with the digital image analysis solution is acceptable for prospective screening of G/GEJ adenocarcinoma patients. The work described here will further advance the companion diagnostic development of our DKK1 RNAscope assay and could generally be used as a guide for the validation of RNAscope assays with digital image quantification.

Taken together, these data demonstrate a clinically validated DKK1 RNAscope CISH laboratory-derived test (LDT) for manual and IA-assisted pathologist interpretation. The DKK1 RNAscope LDT is currently being applied as part of a phase 2 clinical study of DKN-01 in combination with tislelizumab to prospectively identify previously treated G/GEJ adenocarcinoma patients with elevated DKK1 tumor expression (NCT04363801).

DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in gastric/gastroesophageal junction cancer patients. Taken together, our data demonstrate that mDKN-01 has efficacy by blocking the immunosuppressive effects of DKK1 in the tumor microenvironment and provides insight into the clinical activity observed with DKN-01 based treatment. Implications: mDKN-01 reverses a DKK1-mediated innate immune suppression in the tumor microenvironment and has additive efficacy with a PD-1 inhibitor.

The most commonly used drugs, investigated in 3 or more clinical trials included DKN-01 [DKK1 neutralizing monoclonal antibody] (9.9%), PRI-724 [CBP/ β-catenin complex inhibitor] (4%), OMP-54F28 [Decoy Receptor for Wnt lignads] (4%), Vantictumab [monoclonal antibody against Frizzled receptors] (4%), Cirmtuzumab [monoclonal antibody against ROR1] (4%), and BHQ880 [monoclonal antibody against DKK1] (3%). Based on our analysis, we reckon that DKK1 is the most investigated Wnt pathway target in cancer clinical trials, with DKN-01 being the most explored drug. Out of the 91 studies, the highest number of trials were carried out in colorectal cancer, followed by multiple myeloma. The preponderance of the clinical trials in early phases and active status could be the possible reasons for the deficit of Wnt pathway modifiers for cancer therapy in clinical practice.

CGX-1321 significantly reduced tumor burden and enhanced CD8+ T cell levels in ovarian cancer, nevertheless the addition of DKN-01 or anti-PD-1 therapies did not enhance these effects of CGX-1321. Further investigation is needed to determine if CGX-1321 + DKN-01 combination treatment sensitizes pre-clinical ovarian cancer to ICB therapy.

DKN-01 (D), a neutralizing DKK1 antibody, has demonstrated safety and clinical activity in advanced EGC either as a monotherapy or in combination with paclitaxel (pac) or pembrolizumab (pem). Previously we have demonstrated greatest clinical benefit in ICI-naïve, DKK1 high G/GEJ adenocarcinoma treated with D + pem.1 DKK1-high ICI refractory pts treated with D + pem experienced longer PFS and OS compared with pts with low DKK1 expression. DKK1 as a predictive biomarker for DKN-01 is being evaluated in ongoing studies.

DKN-01 (D), a neutralizing DKK1 antibody, has demonstrated safety and clinical activity in advanced EGC either as a monotherapy or in combination with paclitaxel (pac) or pembrolizumab (pem). Previously we have demonstrated greatest clinical benefit in ICI-naïve, DKK1 high G/GEJ adenocarcinoma treated with D + pem.1 DKK1-high ICI refractory pts treated with D + pem experienced longer PFS and OS compared with pts with low DKK1 expression. DKK1 as a predictive biomarker for DKN-01 is being evaluated in ongoing studies.

These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353).

DKN-01 300mg was well tolerated in this combination but did not appear to have additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. Exploratory pharmacokinetic and biomarker data indicate potential antiangiogenic and immunomodulatory activity of DKN-01/chemotherapy and the need for increased dose/intensity. A study with DKN-01 600mg in combination with a PD-1 inhibitor in BTC is ongoing.

P2a, N=72, Recruiting, Leap Therapeutics, Inc. | Not yet recruiting --> Recruiting

We believe this is achieved through an immunomodulatory effect, primarily acting via the innate arm of the immune system. This emphasizes the potential for addressing innate immune resistance and expanding the group of patients who may benefit, possibly in a biomarker-selected manner.

CGX-1321 decreased omental weight and ascites volume, while DKN-01 increased the cellular percentage of NK cells. Both DKN-01 and CGX-1321 increased CD8+ T cells. Wnt-inhibition is therapeutically promising in EOC, and the combination of a PORCN inhibitor with DKN-01 could improve the response to immune checkpoint blockage and further investigation is warranted.

P2a, N=72, Not yet recruiting, Leap Therapeutics, Inc.

Our results suggest that DKK1 inhibition does not affect tumor growth in the ID8 ovarian cancer model. DKK1 overexpression alters anti-tumor immune populations within the tumor microenvironment. Thus, our findings confirm DKK1 as a new therapeutic target in EOC and suggest that DKK1 inhibition may function best in a combinatorial, immune-modulatory therapy.

P2, N=0, Withdrawn, European Organisation for Research and Treatment of Cancer - EORTC | N=123 --> 0 | Not yet recruiting --> Withdrawn

P1, N=151, Active, not recruiting, Leap Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=224 --> 151 | Trial completion date: Dec 2019 --> Dec 2020 | Trial primary completion date: Dec 2019 --> Dec 2020

Patients with recurrent EEC or platinum-resistant/refractory epithelial ovarian cancer (EOC; ≥1 therapy for recurrent disease) were treated with DKN-01 as monotherapy (mono) or in combination with paclitaxel (combo) in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt-signaling alteration. EEC patients more commonly had Wnt-activating mutations, mostly CTNNB1, while a lower frequency was seen in EOC patients. Wnt-activating mutations were associated with improved clinical benefit and longer PFS for DKN-01 based therapies, independent of tumor and treatment type. There were a limited number of deaths as of July 30, 2019, and overall survival follow-up is ongoing.

P2, N=123, Not yet recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Initiation date: Aug 2019 --> Dec 2019

Recently, anti-DKK1 antibody (DKN-01) [D] plus pembrolizumab (P) in GEA tumors has demonstrated clinical activity. Radiomics of GEA tumor metastasis using QTA showed significant correlations between tumor texture, tumor DKK1 mRNA expression and baseline plasma DKK1 suggesting that tumor textures may provide a non-invasive tool for assessing DKK1. Although promising as a imaging biomarker, further studies are required to validate these findings. Clinical trial information: NCT02013154.

Pts were assigned (MD discretion) to receive D (300 mg on Days 1 & 15) or D + paclitaxel (P) (80 mg/m2 on Days 1, 8 and 15) of a 28-day cycle. D and D + P have activity in pts with recurrent gyn cancers; the role of Wnt/β-catenin pathway activation as a potential biomarker for response is currently under study. Clinical trial information: NCT03395080.