Found 2 Presentations For Request "DKN-01"

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Oesophagogastric cancer

1253P - Safety and efficacy of Wnt inhibition with a DKK1 inhibitor, DKN-01, in combination with atezolizumab in patients with advanced oesophagogastric adenocarcinoma: Phase IIa results of the WAKING trial

Presentation Number
1253P
Speakers
  • Fiona S. Turkes (Sutton, United Kingdom)
Date
Mon, 12.09.2022

Abstract

Background

Immune checkpoint inhibitor (ICI) monotherapy has limited efficacy in patients (pts) with mismatch repair proficient (MMRp) oesophagogastric adenocarcinoma (OGA). Dickkopf-1 (DKK1) modulates Wnt/β-Catenin signaling and promotes a T-cell excluded or ‘immune desert’ tumour microenvironment (TME). DKN-01, a DKK1 neutralising antibody, can favourably reprogram the TME by reducing levels of myeloid-derived suppressor cells (MDSCs) and increasing entry of effector T-cells and may improve responses when added to ICI monotherapy.

Methods

This phase IIa study (3+3 design) evaluated the safety and efficacy of DKN-01 (300mg/600mg) and atezolizumab (840mg) given intravenously q2W in pts with pre-treated, anti PD1/PDL1 naïve, MMRp advanced OGA. The primary endpoint was to establish the safety, tolerability, and recommended phase II dose (RP2D) for the efficacy phase. Safety, efficacy, and translational analyses (including intratumoural DKK1/PD-L1, peripheral MDSC and NK cell populations, TCR diversity analysis, tumour genomics and stool microbiome) are ongoing.

Results

Eleven pts were treated on study (5 pts at DKN-01 300mg, 6 at 600mg). Eight pts completed the DLT period (3 at 300mg, 5 at 600mg) and were therefore evaluated for the safety endpoint. No dose limiting toxicities were observed. Of the 11 treated pts, 10 (90.9%) experienced at least one treatment-related AE (TRAE). The most common TRAEs (experienced by ≥ 2 pts) were fatigue (36%), anaemia (18%), hypothyroidism (18%), diarrhoea (18%) and pain (18%). One pt experienced G3 urticaria and 1 experienced an SAE of G2 pneumonitis, both were treatment related. Of the 8 pts evaluated for the safety endpoint, 1 pt (12.5%) had PR and 4 pts (50%) had SD as their best response. No clear trend between peripheral MDSC levels at baseline and during treatment have yet been observed. Additional biomarker work is ongoing.

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.

Clinical trial identification

NCT04166721.

Legal entity responsible for the study

The Royal Marsden Hospital.

Funding

WAKING was collaboratively supported by the imCORE network on behalf of F. Hoffmann-La Roche.

Disclosure

E. Smyth: Financial Interests, Personal, Invited Speaker: Amgen, Bristol-Myers Squibb, Imedex, Merck, Novartis, Prova Education, Servier, TouchIME; Financial Interests, Personal, Other, TSC: Amgen; Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bristol-Myers Squibb, My Personal Therapeutics, Novartis, Roche, Servier, Zymeworks; Financial Interests, Personal, Other, IDMC: Beigene, Zymeworks; Financial Interests, Personal, Expert Testimony: Bristol-Myers Squibb; Financial Interests, Personal, Other, IDMC chair: Everest Clinical Research; Financial Interests, Personal, Officer: EORTC GI Clinical Trials Group; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, Roche, AstraZeneca, Merus, Basilea, MSD; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb. S. Rao: Financial Interests, Personal, Advisory Board: Hoopika, Bayer; Financial Interests, Personal, Expert Testimony: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Merck Serono; Non-Financial Interests, Principal Investigator, Chief investigator phase II and III trials: Incyte. I. Chau: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli-Lilly, MSD, Roche, Merck-Serono, AstraZeneca, OncXerna, Pierre Fabre, Boehinger Ingelheim, Astella, Incyte, GSK, Sotio, Daiichi-Sankyo, Eisai; Financial Interests, Personal, Other, DMC chairman: Five Prime Therapeutics; Financial Interests, Personal, Invited Speaker: Eisai, Eli-Lilly, Servier; Financial Interests, Institutional, Invited Speaker: Cilag-Janssen, Eli-Lilly. N. Starling: Financial Interests, Personal, Advisory Board: GSK, Novartis, MSD Oncology, Servier, AstraZeneca, Pfizer; Financial Interests, Personal, Invited Speaker: Clinical Options, Eli Lilly, Pierre Fabre, Amgen, Merck Serono; Financial Interests, Institutional, Research Grant, Sept 2017 (24m) Paid to institution research: Merck; Financial Interests, Institutional, Research Grant, Nov 2017 (48m) -Paid to institution research fund: AstraZeneca; Financial Interests, Institutional, Research Grant, Jan 2018 - Paid to institution research fund: Pfizer; Financial Interests, Institutional, Research Grant, July 2018 (36m) Paid to institution research fund: BMS. D. Cunningham: Financial Interests, Institutional, Research Grant: MedImmune/AZ, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Leap, Roche; Non-Financial Interests, Advisory Role: OVIBIO. All other authors have declared no conflicts of interest.

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Oesophagogastric cancer

1213P - DKN-01 and tislelizumab + chemotherapy as first-line (1L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial

Presentation Number
1213P
Speakers
  • Samuel J. Klempner (Boston, United States of America)
Date
Mon, 12.09.2022

Abstract

Background

Despite recent approval of anti-PD-1 antibodies as 1L therapy in advanced GEA, benefit is largely limited to PD-L1 combined positive scores (CPS) ≥5 patients (pts); novel therapeutic approaches are needed. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated activity in GEA pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival.

Methods

Phase IIa single arm trial investigating DKN-01 300 mg (D) + tislelizumab (TS) + CAPOX as 1L therapy in advanced HER2(-) GEA regardless of DKK1 status. Tumoral DKK1 mRNA expression was assessed by a chromogenic in situ hybridization RNAscope assay and assigned an H-score (0-300). Primary endpoint was ORR in modified intent to treat (mITT) population (>1 dose D); secondary endpoints included PFS and OS in intent to treat (ITT) population overall and by DKK1 expression: high (H-score ≥35) vs low.

Results

25 pts enrolled (01 Sept 2020 - 08 Apr 2021). Median age 61 years (22, 80); 17 pts gastroesophageal junction adenocarcinoma; 8 pts gastric cancer. 21 GEA pts had RNAscope DKK1 expression; 57% were DKK1-high. 22 of 25 pts had vCPS: 73% were vCPS <5. Median duration of treatment 11.3 mos. 7 pts on therapy and only 9 of 25 pts have died. 12 mo survival: 76%. 14 pts (56%) experienced D-TRAEs (treatment related adverse events), most (96%) were G1/2. Most common regimen TRAEs were nausea (72%), fatigue (64%), and diarrhoea (56%). 5 pts experienced ≥G3 D-TRAEs: hypophosphatemia (2), pulmonary embolism (2, one regimen related G5), neutropenia (1), diarrhoea (1).

ORR mITT*, n=22 (n,%) Median DoR, mos (n=15)* Median PFS, mos, ITT (n=25)
CR PR SD NE
Overall 15 (68) 1 (5) 14 (64) 6 (27) 1 (5) 10.0 11.3
DKK1 high, n=10 9 (90) - 9 (90) - 1 (10) 10.6 11.6
DKK1 low, n=9 5 (56) 1 (11) 4 (44) 4 (44) - 10.6 12.0
DKK1 unk, n=3 1 (33) - 1(33) 2 (67) - 7.0 8.4

*4 responders ongoing (2 high, 2 low)

Conclusions

D/TS + CAPOX is a well-tolerated, active 1L combination, including in DKK1-high and CPS low patients, aggressive subpopulations of GEA. With only 36% of pts deceased as of the data cut, OS is not mature. Further study with DKN-01 plus standard of care therapy in IL GEA is warranted.

Clinical trial identification

NCT04363801.

Legal entity responsible for the study

Leap Therapeutics, Inc.

Funding

Leap Therapeutics, Inc.

Disclosure

S.J. Klempner: Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Eli Lilly, Merck, Bristol Myers Squibb, Astellas, Daiichi Sankyo, Pieris; Financial Interests, Personal, Advisory Board, One Time Advisory Board: Natera; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x 1: Mersana, Sanofi-Aventis; Financial Interests, Personal, Stocks/Shares, Stock Ownership: Turning Point Therapeutics; Financial Interests, Personal, Stocks/Shares, Early investor, company is not public: MBrace; Financial Interests, Institutional, Invited Speaker, National PI for trial: Leap Therapeutics; Financial Interests, Personal and Institutional, Invited Speaker, Local PI for trial, also served on advisory board as noted above: Astellas; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker, Trial PI: Silverback; Non-Financial Interests, Advisory Role, Medical-Scientific Advisory Board Member: Debbies Dream Foundation; Non-Financial Interests, Advisory Role, Member of Scientific Advisory Board: Hope for Stomach Cancer; Non-Financial Interests, Other, Member of Gastric and Esophageal NCCN Guideline Committees: NCCN. J. Chao: Financial Interests, Personal, Advisory Board: Merck, Amgen, Daiichi Sankyo, Macrogenics, Bristol Myers Squibb, Astellas, Turning Point Therapeutics; Financial Interests, Personal, Invited Speaker: Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting: Lilly, AstraZeneca, Ono Pharmaceuticals, Roche; Financial Interests, Institutional, Funding: Merck, Brooklyn Immunotherapeutics. H. Uronis: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Other, DSMB: Astra Zeneca; Financial Interests, Institutional, Invited Speaker: Merck, Leap Therapeutics, Bristol-Myers Squibb, Merrimack Pharmaceuticals. C. Sirard: Financial Interests, Personal, Full or part-time Employment, Chief Medical Officer: Leap Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares, Full time employee/Chief Medical Officer: Leap Therapeutics, Inc.; Financial Interests, Personal, Other, Pending and issued patents with DKN-01: Leap Therapeutics, Inc.. M. Kagey: Financial Interests, Personal, Full or part-time Employment, Full time employee: Leap Therapeutics; Financial Interests, Personal, Stocks/Shares, Stock option holder: Leap Therapeutics. J. Baum: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics; Financial Interests, Personal, Stocks/Shares: Leap Therapeutics. J. Song: Financial Interests, Personal, Full or part-time Employment: BeiGene; Financial Interests, Personal, Stocks/Shares: BeiGene. J. Wang: Financial Interests, Personal, Full or part-time Employment: BeiGene; Financial Interests, Personal, Stocks/Shares: BeiGene. M.B. Sonbol: Financial Interests, Institutional, Research Grant, Research support to institution supporting ACCRU 1810 study: Taiho, Eli Lilly. Z.A. Wainberg: Financial Interests, Personal, Advisory Role: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Institutional, Research Grant: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Roche/Genentech, Array/Pfizer. J.A. Ajani: Financial Interests, Personal, Advisory Role: BMS, Merck, Taiho, AZ, Daiichi, Novartis, Amgen, Gilead, Astellas, Zymeworks, Beigene, Innovent, OncLive, Geneos, Arcus, Servier, Grail; Financial Interests, Institutional, Funding: Leap Therapeutics, BMS, Astellas, Amgen, Taiho, DeltaFly, Zymeworks, Prolinx, Gilead, Daiichi, LaNova, Macrogenics ; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Other: NCCN.

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