inlexisertib (DCC-3116) / Ono Pharmaceutical, Deciphera Pharmaceuticals - LARVOL DELTA

ULK1's role in cancer progression and its emerging therapeutic potential. (PubMed, Cancer Biol Ther) - "The first clinical agent, DCC-3116, demonstrates on-target engagement with acceptable tolerability and is being evaluated in combinations where therapy induces autophagy. Here, we review ULK1 as a regulator of cancer progression, synthesizing pan-cancer clinical and functional evidence alongside the evolving pharmacology of ULK1 modulation to define the settings in which its targeted inhibition may be most effectively translated."

Journal • Review • Oncology • ULK1

Divergent Role of ULK1 to Balance Mitochondrial Homeostasis and Bioenergetics in Ovarian Cancer Spheroids. (PubMed, Cancers (Basel)) - "These data show that ULK1 differentially regulates mitochondrial degradation across EOC spheroid models through potential mechanisms alternative to canonical autophagy machinery, while reshaping spheroid metabolism and revealing potential therapeutic vulnerabilities in advanced EOC."

Journal • Epithelial Ovarian Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • HK2 • ULK1

Dissecting lysosomal metabolic dependencies in pancreatic cancer through functional genomics (AACR 2026) - "To address these issues, here we perform parallel metabolism-focused CRISPR activation and knockout screens using 8 different autophagy or lysosome inhibitors in pancreatic cancer cell lines. From these, we determined that iron homeostasis is primarily affected by agents that affect lysosomal pH, such as bafilomycin A1 and Ammonium, but not by other inhibitors of lysosomal function such as apilimod, ESK981, or chloroquine, or by ULK1 inhibitors ULK101, SBI-0206965, or DCC-3116. Pairing the CRISPR screen data with transcriptomics, we further identified that lipid homeostasis was affected by all lysosome inhibitors but not ULK inhibitors."

Oncology • Pancreatic Cancer • Solid Tumor

Study of Inlexisertib (DCC-3116) in Participants With RAS/MAPK Pathway Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=91 | Terminated | Sponsor: Deciphera Pharmaceuticals, LLC | Phase classification: P1/2 ➔ P1 | N=144 ➔ 91 | Trial completion date: Aug 2028 ➔ Mar 2026 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2027 ➔ Mar 2026; Trial terminated due to business decision, not based on any safety or efficacy concerns.

Enrollment change • First-in-human • Monotherapy • Phase classification • Trial completion date • Trial primary completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KRAS • NF1

Inhibition of ULK and KRASG12C control tumor growth in preclinical models of lung cancer (AACR 2024) - "Consequently, we have generated genetically engineered mouse models (GEMMs) of KRASG12C-driven lung cancer in which LKB1 is silenced to further investigate the role of LKB1 in the autophagy response of KRASG12C-driven lung cancers to pathway-targeted blockade of oncogenic KRAS signaling. We have treated KRASG12C-driven GEMMs with sotorasib and/or DCC-3116 to test the sensitivity of lung tumors to these treatment options."

Preclinical • Lung Cancer • Oncology • Solid Tumor • KRAS • STK11

A Study of Inlexisertib (DCC-3116) in Combination With Anticancer Therapies in Participants With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=94 | Recruiting | Sponsor: Deciphera Pharmaceuticals, LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • KIT • PDGFRA

A phase I/II study of inlexisertib (DCC-3116) in combination with ripretinib for patients (pts) with advanced gastrointestinal stromal tumor (GIST): Expansion cohort design (Sarcoma-RC 2026) - P1/2 | "In the INTRIGUE trial, the primary endpoint of superior progression-free survival with ripretinib vs sunitinib in second-line (2L) advanced GIST was not met; however, ripretinib showed comparable efficacy and more favorable safety...Trial Design Pts with KIT exon 11–mutant GIST and disease progression on or intolerance to first-line imatinib will be enrolled and treated with inlexisertib 400 mg and ripretinib 150 mg once daily...Legal entity responsible for the study Deciphera Pharmaceuticals, LLC. Funding Deciphera Pharmaceuticals, LLC, a member of ONO Pharma."

Clinical • Combination therapy • Metastases • P1/2 data • Stroma • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • PDGFRA

ULK1 promotes metastatic progression in experimental models of epithelial ovarian cancer. (PubMed, Oncogene) - "To investigate this, we utilized CRISPR/Cas9 technology to delete ULK1 in EOC cell lines OVCAR8, HEYA8, ES2 and the fallopian tube epithelial cell line FT190. Treatment of metastatic patient-derived organoids with the clinical ULK1 inhibitor DCC-3116, MEK inhibitor trametinib, or mTORC1/2 inhibitor AZD-8055 reduced viability in a subset of these samples, reflecting inter-patient heterogeneity and need for biomarker-guided selection. Overall, this study highlights ULK1 as a critical regulator of multiple steps of EOC disease progression, underscoring its potential as a therapeutic target in advanced ovarian cancer."

Journal • Epithelial Ovarian Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BECN1 • ULK1

Discovery of novel ULK1 inhibitors by virtual screening, synthesis, in vitro assay and molecular dynamics simulations. (PubMed, Bioorg Chem) - "Through molecular fingerprint similarity and shape-based screenings of the ChEMBL database, along with fragment growth modifications of DCC-3116, three datasets comprising a total of 1.5 million compounds were generated...Binding free energy calculations indicated that the interactions between the candidate compounds and ULK1 were either stronger or comparable to those of SBI-0206965. Overall, these results suggest that SX1-SX3, and D1-D5 were promising ULK1 inhibitors, providing a solid foundation for further development as potential anticancer drugs."

Journal • Preclinical • Oncology

A Phase 1/2 Study of Inlexisertib (DCC-3116) in Patients With RAS/MAPK Pathway Mutant Solid Tumors (clinicaltrials.gov) - P1/2 | N=144 | Active, not recruiting | Sponsor: Deciphera Pharmaceuticals, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • First-in-human • Monotherapy • Colorectal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRAF • KRAS • NF1 • NRAS

DCC-3116 IN COMBINATION WITH RIPRETINIB FOR PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMOR: A PHASE 1/2 STUDY (CTOS 2024) - P1/2 | "In the INTRIGUE trial, ripretinib demonstrated comparable efficacy and more favorable safety compared with sunitinib in second-line advanced GIST...In part 2, second-line patients with confirmed GIST with a KIT exon 11 mutation who experienced disease progression on or intolerance to first-line imatinib will be enrolled... N/A Trials in progress"

Clinical • Combination therapy • Metastases • P1/2 data • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • PDGFRA

A Study of DCC-3116 in Combination with Anticancer Therapies in Participants with Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=94 | Recruiting | Sponsor: Deciphera Pharmaceuticals, LLC | Trial completion date: Jun 2027 ➔ Mar 2029

Trial completion date • Gastrointestinal Cancer • Oncology • Sarcoma • BRAF • KIT • PDGFRA

A patent review of UNC-51-like kinase 1/2 inhibitors (2019-present). (PubMed, Expert Opin Ther Pat) - "Despite the great success of ULK1/2 inhibitors development, ULK1/2 inhibitors are ATP competitive inhibitors of aminopyrimidines currently, and most ULK1/2 inhibitors are still in the preclinical research stage, with only DCC-3116 entered clinical research. Therefore, developing highly selective ULK1/2 inhibitors with low side effects and high bioavailability remains a challenging and promising research direction."

Journal • Review • Oncology

DCC-3116 In Combination with Sotorasib in Advanced or Metastatic KRASG12C-Mutant Cancers: First-in-human Phase 1/2 Study (IASLC-WCLC 2024) - P1/2 | "Secondary endpoints for both parts include progression-free survival, duration of response, and pharmacokinetics; exploratory endpoints include pharmacodynamics. Part 1 of this study is currently enrolling patients."

Combination therapy • Metastases • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Inhibition of ULK1/2 and KRASG12C controls tumor growth in preclinical models of lung cancer. (PubMed, Elife) - "Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC)...Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRASG12C-driven lung cancer cell proliferation in vitro and superior tumor control in vivo. Additionally, in genetically engineered mouse models of KRASG12C-driven NSCLC, inhibition of either KRASG12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRASG12C in lung cancer."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

DCC-3116 in combination with ripretinib for patients with advanced gastrointestinal stromal tumor: A phase 1/2 study. (ASCO 2024) - P1/2 | "In the INTRIGUE trial, ripretinib demonstrated comparable efficacy and more favorable safety compared with sunitinib in second-line advanced GIST...In part 2, second-line pts with confirmed GIST with a KIT exon 11 mutation and disease progression on or intolerance to first-line imatinib will be enrolled...The primary objective of part 2 is to determine the objective response rate per modified Response Evaluation Criteria in Solid Tumors version 1.1. The study is currently enrolling."

Clinical • Combination therapy • Metastases • P1/2 data • Stroma • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Infectious Disease • Oncology • Sarcoma • PDGFRA

Ono Announces Results of Tender Offer to Acquire Deciphera Pharmaceuticals and Completion of Acquisition of Deciphera (a Wholly Owned Subsidiary of Ono) (PRNewswire) - "Ono Pharmaceutical...today announced that it has successfully completed the tender offer, previously announced on April 30, 2024 to acquire all outstanding shares of common stock of a US biopharmaceutical company, Deciphera Pharmaceuticals, Inc...for US$25.60 per share (total amount of approximately US$2.4 billion) net to the seller in cash, without interest thereon and less any applicable withholding taxes, through its wholly owned subsidiary, Topaz Merger Sub, Inc...established in the State of Delaware, United States, solely for the purpose of engaging in the transactions contemplated in the Merger Agreement....'Through this acquisition, we will leverage Deciphera's excellent research and development capabilities in the oncology field and its sales power in Europe and the United States, and work to further accelerate the expansion of our pipeline and global expansion, which are part of our growth strategies.'"

M&A • Gastrointestinal Stromal Tumor • Graft versus Host Disease • Hematological Malignancies • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Tenosynovial Giant Cell Tumor

A Phase 1/2 Study of DCC-3116 in Patients With RAS/MAPK Pathway Mutant Solid Tumors (clinicaltrials.gov) - P1/2 | N=173 | Recruiting | Sponsor: Deciphera Pharmaceuticals LLC | N=323 ➔ 173 | Trial completion date: Oct 2024 ➔ Aug 2028 | Trial primary completion date: Apr 2024 ➔ Aug 2027

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRAF • KRAS • NF1 • NRAS

Deciphera Pharmaceuticals Announces Oral Presentation of Results from MOTION Pivotal Phase 3 Study of Vimseltinib in Patients with Tenosynovial Giant Cell Tumor (TGCT) at the 2024 ASCO Annual Meeting and Online Publication in The Lancet (Businesswire) - "This is a phase 1/2, multicenter study designed to evaluate the safety, tolerability, and efficacy of DCC-3116 in combination with ripretinib. In Part 1, eligible patients will receive escalating oral doses of DCC-3116 combined with ripretinib 150 mg once daily (QD); the safety will be evaluated and the recommended phase 2 dose (RP2D) will be determined. In Part 2, eligible patients will receive the RP2D of DCC-3116 in combination with ripretinib 150 mg QD; antitumor activity will be evaluated. The trial is currently enrolling in the phase 1 dose escalation portion."

Trial status • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Solid Tumor

A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=94 | Recruiting | Sponsor: Deciphera Pharmaceuticals LLC | N=170 ➔ 94

Combination therapy • Enrollment change • Metastases • Gastrointestinal Cancer • Oncology • Sarcoma • BRAF • KIT • PDGFRA

Discovery of DCC-3116. A selective, first-in-class ULK inhibitor for cancer therapy (ACS-Sp 2024) - "We disclose herein the development of DCC-3116, a potent and selective inhibitor of ULK1/2 and report on its promising preclinical activity in a series of in vitro and in vivo studies. DCC-3116 is currently in Phase 1 clinical development in combination with RTK pathway inhibitors in patients with advanced or metastatic solid tumors with mutations in the pathway."

Oncology • Solid Tumor

Deciphera Pharmaceuticals Announces Planned 2024 Corporate Milestones Supporting Evolution to a Self-Sustaining, Multi-Product Company (Businesswire) - "DCC-3116: The Company expects to select a recommended Phase 2 dose for expansion cohort(s) for DCC-3116, an investigational switch-control kinase inhibitor of ULK1/2 designed to inhibit autophagy, in 2024; The Company has prioritized the development of DCC-3116 in combination with sotorasib and with QINLOCK and discontinued development of the encorafenib and cetuximab combination cohort prior to enrollment in any clinical studies as well as the two MEK combination cohorts."

Trial status • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Solid Tumor

Deciphera Pharmaceuticals Announces Third Quarter 2023 Financial Results (Businesswire) - "DCC-3084: Expects to submit an Investigational New Drug (IND) application to the FDA for its pan-RAF inhibitor, DCC-3084, by year end 2023. DCC-3009: Expects to submit an IND application to the FDA for its pan-KIT inhibitor, DCC-3009, in the first half of 2024....Total revenue for the third quarter of 2023 was $43.3 million, which includes $41.8 million of net product revenue of QINLOCK and $1.5 million of collaboration revenue compared to $36.0 million of total revenue, including $32.3 million of net product revenue of QINLOCK and $3.7 million of collaboration revenue, for the same period in 2022....Research and development expenses for the third quarter of 2023 were $62.5 million, compared to $47.5 million for the same period in 2022. The increase was primarily due to an increase in clinical study costs for QINLOCK and clinical study costs related to the Phase 1/2 study of DCC-3116."

Commercial • IND • Sales • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Deciphera Pharmaceuticals Announces Second Quarter 2023 Financial Results (Businesswire) - "Expects to announce top-line results from the MOTION pivotal Phase 3 study of vimseltinib, an investigational, orally administered, potent, and highly selective switch-control kinase inhibitor of CSF1R for the potential treatment of tenosynovial giant cell tumor (TGCT) in the fourth quarter of 2023. Expects to present updated data from the Phase 1/2 study of vimseltinib in the fourth quarter of 2023....Expects to submit an investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA) for DCC-3084 in the fourth quarter of 2023....Expects to submit an IND to the FDA for DCC-3009 in the first half of 2024.... Research and development expenses for the second quarter of 2023 were $58.3 million, compared to $44.9 million for the same period in 2022. The increase was primarily due to an increase in clinical study costs related to the Phase 1/2 study of DCC-3116, the MOTION Phase 3 study and Phase 1 /2 study of vimseltinib, and clinical study costs for QINLOCK."

Commercial • IND • P1/2 data • P3 data: top line • Oncology • Solid Tumor

A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=170 | Recruiting | Sponsor: Deciphera Pharmaceuticals LLC | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Sarcoma • Solid Tumor • BRAF • KIT • PDGFRA