sirexatamab (DKN-01) / Eli Lilly, Leap Therap - LARVOL DELTA

DKN-01 and atezolizumab as second or third-line therapy in advanced mismatch repair proficient (MMRp) oesophagogastric adenocarcinoma (OGA): WAKING trial (ESMO-GI 2025) - No abstract available

Metastases • Mismatch repair • pMMR • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Leap Therapeutics to Host Virtual KOL Event to Discuss Sirexatamab (DKN-01) in Second-line Patients with Advanced Microsatellite Stable Colorectal Cancer (PRNewswire) - "Dr. Wainberg will connect with Leap's Chief Medical Officer, Cynthia Sirard, MD, to discuss the unmet need and how sirexatamab (DKN-01) may improve upon the current treatment landscape for previously treated patients with advanced microsatellite stable (MSS) colorectal cancer (CRC). The event will focus on reviewing the positive data from Part B of the Phase 2 DeFianCe study of sirexatamab in second-line patients with advanced MSS CRC."

P2 data • Colorectal Cancer

WaKING: Wnt and checKpoint INhibition in Gastric Cancer (clinicaltrials.gov) - P1/2 | N=52 | Active, not recruiting | Sponsor: Royal Marsden NHS Foundation Trust | Trial completion date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Checkpoint inhibition • Mismatch repair • pMMR • Trial completion date • Trial primary completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Solid Tumor

Leap Therapeutics Reports Positive Updated Data from Sirexatamab Colorectal Cancer Study (PRNewswire) - P2 | N=189 | DeFianCe (NCT05480306) | Sponsor: Leap Therapeutics, Inc. | "In patients with high DKK1 levels (upper quartile, n=44), the sirexatamab Experimental Arm has a statistically significant 32% higher ORR, 3.5 month longer PFS, and OS compared to the Control Arm; In patients who had not received prior anti-VEGF therapy (n=95), the sirexatamab Experimental Arm has a statisticially significant 22% higher ORR and 2.6 month longer PFS compared to the Control Arm, with OS not mature but favoring the sirexatamab Experimental Arm; Across the intent-to-treat population (n=188), the sirexatamab Experimental Arm has improved ORR compared to the Control Arm, with the primary endpoint of PFS still to mature due to the higher number of patients remaining on sirexatamab driving separation after the median."

P2 data • Colorectal Cancer

Leap Therapeutics Reports Initial Clinical Data from Part B of the DeFianCe Study (PRNewswire) - P2 | N=189 | DeFianCe (NCT05480306) | Sponsor: Leap Therapeutics, Inc | "Patients treated with sirexatamab plus bevacizumab and chemotherapy (Experimental Arm, n=94) had ORR of 35% and disease control rate (DCR) of 86%, compared to an ORR of 23% and DCR of 84% in patients treated with bevacizumab and chemotherapy alone (Control Arm, n=94); Patients treated in the Experimental Arm (n=71) had an ORR of 38%, compared to an ORR of 25% in the Control Arm (n=73); Patients in the Experimental Arm with DKK1 levels above the median (n=49) had an ORR of 39%, compared to 22% ORR in the Control Arm (n=36); With only 3 months follow-up on the final patients enrolled and mean duration on study of approximately 6 months, PFS is not yet mature."

P2 data • Colorectal Cancer

Leap Therapeutics Reports Initial Clinical Data from…Part C of the DisTinGuish Study (PRNewswire) - P2 | N=232 | DisTinGuish (NCT04363801) | Sponsor: Leap Therapeutics, Inc | "While demonstrating activity in biomarker populations, the study did not generate a clear positive signal and will be negative on the primary PFS endpoints when the study completes, resulting in the decision not to move forward with Phase 3 studies in gastric cancer...Part C enrolled 170 first-line, HER2-negative patients...Across the ITT population (n=170), patients treated with sirexatamab plus tislelizumab and chemotherapy (Experimental Arm, n=85) had a confirmed ORR of 52% by both IA and BICR, while patients treated with tislelizumab and chemotherapy alone (Control Arm, n=85) had a confirmed ORR of 56% by IA and 42% by BICR; In the ITT population, preliminary median PFS in the Experimental Arm was 9.72 months by BICR and 7.66 months by IA compared to 11.99 months by BICR and 10.41 months by IA in the Control Arm; Sirexatamab plus tislelizumab and chemotherapy was well tolerated."

P2 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

Leap Therapeutics Reports Third Quarter 2024 Financial Results (PRNewswire) - "Leap Highlights: Completed enrollment in the expanded randomized controlled Part B of the Phase 2 DeFianCe study evaluating DKN-01, Leap's anti-DKK1 monoclonal antibody, in combination with standard of care bevacizumab and chemotherapy in second-line patients with advanced colorectal cancer (CRC); data expected in mid-2025; Patient follow-up continuing in the randomized controlled Part C of the Phase 2 DisTinGuish study evaluating DKN-01 in combination with tislelizumab and chemotherapy in first-line patients with advanced gastroesophageal junction (GEJ) and gastric cancer; data expected in late 2024 or early 2025."

P2 data • Trial status • Colorectal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

Leap Therapeutics Reports Third Quarter 2024 Financial Results (PRNewswire) - "Research and development expenses were $14.9 million for the third quarter 2024, compared to $11.5 million for the same period in 2023. The increase of $3.4 million was primarily due to an increase of $1.7 million in manufacturing costs related to clinical trial material and manufacturing campaigns, and an increase of $0.8 million in clinical trial costs due to patient enrollment, the duration of patients on study, the enhancement of correlative studies, increase in site activity associated with Part C of the DisTinGuish study, and the expansion of the size of Part B of the DeFianCe study."

Commercial • Colorectal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish (J Clin Oncol) - P2 | N=232 | DisTinGuish (NCT04363801) | Sponsor: Leap Therapeutics, Inc. | "Between September 18, 2020, and April 8, 2021, 25 patients were enrolled....The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%."

P2 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish. (PubMed, J Clin Oncol) - P2 | "DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801)."

Combination therapy • IO biomarker • Journal • Metastases • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • DKK1 • HER-2 • PD-L1

Characterization of cell states in biliary tract cancers identifies mechanisms of therapeutic resistance in a phase II trial of DKN-01/nivolumab. (PubMed, medRxiv) - P2 | "Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials."

Journal • P2 data • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • DKK1

[PREPRINT] Characterization of cell states in biliary tract cancers identifies mechanisms of therapeutic resistance in a phase II trial of DKN-01/nivolumab (medRxiv) - "We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab."

P2 data • Preprint • Biliary Tract Cancer • Oncology • Solid Tumor

DeFianCe: Phase 2 Study of DKN-01 in Colorectal Cancer (clinicaltrials.gov) - P2 | N=189 | Active, not recruiting | Sponsor: Leap Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Leap Therapeutics Announces Completion of Enrollment in Part B of the DeFianCe Study of DKN-01 for the Treatment of Colorectal Cancer Patients (PRNewswire) - "Leap Therapeutics, Inc...announced that enrollment of 188 patients has been completed in the randomized controlled Part B of the DeFianCe study evaluating DKN-01, Leap's anti-Dickkopf-1 (DKK1) antibody, in combination with standard of care bevacizumab and chemotherapy as a second-line treatment for patients with advanced colorectal cancer (CRC)....'We look forward to sharing initial data from Part B, including the subpopulation of patients with left-sided CRC, in mid 2025'."

Enrollment closed • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

DKN-01 Suppresses Gastric Cancer Progression Through Activating cGAS-STING Pathway to Block Macrophage M2 Polarization. (PubMed, Appl Biochem Biotechnol) - "Moreover, DKN-01 activated the cGAS/STING pathway, while the inactivation of cGAS-STING pathway using RU.521 reversed the inhibition of tumor growth in vivo and macrophage M2 polarization caused by DKN-01. This study reveals that DKN-01 suppresses GC tumor growth through activating cGAS-STING pathway to block macrophage M2 polarization."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • DKK1

Leap Therapeutics Reports Second Quarter 2024 Financial Results (PRNewswire) - P2 | N=200 | DeFianCe (NCT05480306) | Sponsor: Leap Therapeutics, Inc. | "Key Updated Part A Findings (as of June 7, 2024 data cut-off): ORR among response-evaluable patients (n=27) was 33% and disease control rate (DCR) was 93%, including 9 PRs and 16 patients with a best response of SD. Median progression-free survival (PFS) was unchanged at 6.3 months....DKN-01 plus bevacizumab and chemotherapy was well-tolerated, with a majority of DKN-01 related events being low grade (Grade 1/2)....Enrollment in Part B of the DeFianCe Study in CRC patients is ongoing and expected to be completed by the end of September 2024."

Enrollment status • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Solid Tumor

WaKING: Wnt and checKpoint INhibition in Gastric Cancer (clinicaltrials.gov) - P1/2 | N=52 | Active, not recruiting | Sponsor: Royal Marsden NHS Foundation Trust | Recruiting ➔ Active, not recruiting | Trial primary completion date: May 2024 ➔ Dec 2024

Checkpoint inhibition • Enrollment closed • Metastases • Mismatch repair • Trial primary completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Leap Therapeutics Reports Second Quarter 2024 Financial Results (PRNewswire) - "Randomized controlled Part C of the DisTinGuish study in patients with GEJ and gastric cancer is ongoing, with initial data expected in Q4 2024 or early 2025."

P2 data • Trial status • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

DeFianCe: Phase 2 Study of DKN-01 in Colorectal Cancer (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Leap Therapeutics, Inc. | N=150 ➔ 200

Enrollment change • Metastases • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

DeFianCe: Phase 2 Study of DKN-01 in Colorectal Cancer (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Leap Therapeutics, Inc. | Trial completion date: Aug 2024 ➔ Dec 2025 | Trial primary completion date: Mar 2024 ➔ Dec 2025

Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Leap Therapeutics Reports First Quarter 2024 Financial Results (PRNewswire) - "Expanded the ongoing randomized controlled Part B of the DeFianCe study from 130 patients to 180 patients to enhance the statistical power for patients with left-sided CRC; enrollment now expected to be completed in late Q3 or early Q4 2024; Completed enrollment in the randomized controlled Part C of the Phase 2 DisTinGuish study evaluating DKN-01 in combination with tislelizumab and chemotherapy in patients with advanced gastroesophageal junction (GEJ) and gastric cancer; first randomized controlled data for DKN-01 expected in the second half of 2024 or early 2025,"

Enrollment status • P2 data • Colorectal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Leap Therapeutics Announces $40 Million Private Placement (PRNewswire) - "Leap Therapeutics, Inc...announced it has entered into a securities purchase agreement with a select group of institutional investors to issue and sell an aggregate of 12,660,993 shares of its common stock...at a price of $2.82 per share...Leap anticipates the gross proceeds from the private placement will be approximately $40 million, before deducting any offering-related expenses....Leap intends to use the net proceeds from the financing to fund the continued development of its lead monoclonal antibody program, DKN-01, by expanding the randomized controlled Part B of the DeFianCe Study in patients with second-line colorectal cancer from 130 to 180 patients, by enabling data to mature in the randomized controlled Part C of the DisTinGuish study in patients with first-line gastric cancer, and by manufacturing clinical trial material to permit Phase 3 readiness, and for working capital and general corporate purposes."

Financing • Trial status • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Study of the Combination of DKN-01 and Nivolumab in Previously Treated Patients With Advanced Biliary Tract Cancer (BTC) (clinicaltrials.gov) - P2 | N=15 | Terminated | Sponsor: 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.

Enrollment change • Metastases • Trial termination • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Leap Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results (PRNewswire) - "DKN-01 Development Update...The Company expects the 130 patient randomized controlled Part B to complete enrollment in mid-2024. As of March 15, 2024, 80 patients have enrolled in Part B....Part C of the DisTinGuish study (NCT0436380) is a Phase 2, randomized, open-label, multicenter study of DKN-01 in combination with tislelizumab and chemotherapy in first-line patients with advanced gastroesophageal adenocarcinoma....The Company expects to report initial data from Part C of the DisTinGuish study in mid-2024."

Enrollment status • P2 data • Colorectal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Targeted Agents in Esophagogastric Cancer Beyond Human Epidermal Growth Factor Receptor-2. (PubMed, Hematol Oncol Clin North Am) - "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."

Journal • Review • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18 • HER-2