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741 TWT-101: a first-in-clinic study of CFI-402411, a hematopoietic progenitor Kinase-1 (HPK1) inhibitor, as single agent or combined with pembrolizumab in subjects with advanced solid malignancies
  1. Kyriakos P Papadopoulos1,
  2. Scott A Laurie2,
  3. Alexander Spira3,
  4. Siqing Fu4,
  5. Erika Hamilton5,
  6. Brigette Ma6,
  7. Judy S Wang7,
  8. Manish Sharma8,
  9. Quincy Chu9,
  10. Anna Spreafico10,
  11. Mark R Bray11,
  12. Dih-Yih Chen12,
  13. Emily Roberts-Thomson12,
  14. Roger Sidhu12 and
  15. Omid Hamid13
  1. 1START San Antonio, San Antonio, TX, USA
  2. 2The Ottawa Hospital Cancer Center, Ottawa, ON, Canada
  3. 3Virginia Cancer Specialists, Fairfax, VA, USA
  4. 4The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  5. 5Sarah Cannon Research Institute, Nashville, TN, USA
  6. 6The Chinese University of Hong Kong, Hong Kong, Hong Kong
  7. 7Florida Cancer Specialists/SCRI, Sarasota, FL, USA
  8. 8START Midwest, Chicago, IL, USA
  9. 9University of Alberta, Edmonton, AB, Canada
  10. 10Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
  11. 11Treadwell Therapeutics, Toronto, ON, Canada
  12. 12Treadwell Therapeutics Inc, New York, NY, USA
  13. 13The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, CA, USA


Background CFI-402411, a potent HPK1 inhibitor, may promote T-cell response to tumors through a variety of mechanisms that enhance T-cell function in the cancer immunity cycle, and potentially in settings where antigens are expressed poorly and heterogeneously.1 Preliminary results demonstrated tolerable safety profile with efficacy signals in select tumor types.2

Methods In this ongoing phase 1/2 study, part A evaluates CFI-402411 daily dose (3+3 design) and dose expansion; part B evaluates CFI-402411 in combination with pembrolizumab (200mg) as BOIN design and dose expansion in pembrolizumab eligible tumors. Dose limiting toxicity (DLT) is any grade ≥3 toxicity in cycle 1. Starting dose was 80mg.

Results At 02-May-2023 the study enrolled 59 patients (pts; A, 40pts; B, 19pts). In US, checkpoint inhibitor (CPI) pretreated patients were eligible. Diagnoses in ≥2pts for A: colorectal (11pts), melanoma (6pts), pancreatic (5pts) and non-small cell lung and prostate (2pts each) cancers; for B: head and neck squamous cell (HNSCC; 3pts) and esophageal, non-small cell lung and small cell lung cancers (2pts, each). Part A tested 9 dose levels (80 - 800mg). B tested 5 dose levels (60 - 400mg) to date. Immune-related AEs (irAE) were reported in 7 pts (A; 18%) and 5 pts (B; 26%). Grade ≥3 AEs occurred in 25 pts (A: 63%) and 10pts (B: 53%). SAE’s occurred in 21 pts (A: 53%) and 11 pts (B: 58%). Diarrhea was the most common TEAE (A: 73%; B: 47%), related AE (A: 63%; B: 42%), irAE (A: 15%; B: 11%), and grade ≥3 AE in A (18%). Most common grade ≥3 AE in B was pulmonary embolism (PE) and AST increase (11% both). The most common SAE was sepsis (A: 15%) and PE (B: 11%). Diarrhea was the most common DLT occurring at 400mg+pembro; 800mg, 720mg, 640mg monotherapy doses. Disease control rates (CR, PR, or SD ≥ 6 weeks from baseline) at 3 months were 18% (A) and 29% (B). Two HNSCC pts achieved a PR (A: 400mg) and confirmed CR (B: 60mg+pembro). A third HNSCC pt’s (B: 400mg+pembro) tumor lesion size reduced 16% at week 5 and pt remains on study. One RCC pt achieved long term SD, 2 years. All 4 pts had prior CPI exposure.

Conclusions CFI-402411 is well-tolerated with a manageable AE profile. Responses as monotherapy and in combination with CPI in CPI exposed patients were seen. Monotherapy part A expansion at 560 mg is underway in HNSCC and RCC.

Acknowledgements Treadwell Therapeutics would like to thank both the patients and the research staff at enrolling centers who have helped to bring this novel therapy to the clinic.

Trial Registration NCT04521413


  1. You D, Hillerman S, Locke G, et al. Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor. J Immunother Cancer 2021;9(1):e001402

  2. Papadopoulos K, Fu S, Hamilton E, et al. TWT-101: a first-in-clinic, phase 1/2 study of CFI-402411, a hematopoietic progenitor kinase-1 (HPK1) inhibitor, as a single agent and in combination with pembrolizumab in subjects with advanced solid malignancies. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0750

Ethics Approval This study obtained ethics approvals; Papadopoulos; ID: Pro00051609 Fu; ID2020–0678 Hamilton; ID: Pro00051611 Spira; ID: Pro00043629 Laurie; CTO Project ID 3320 Wang; ID: Pro00051611 Ma; CREC Ref: 2020.367-T Spreafico; CTO Project ID 3320 Sharma; ID Pro00051609 Chu; ID: HREBA.CC-20–0504_REN1 Hamid; IRB: 2020236

Consent As evidenced by verified clinical database information all subjects gave informed consent before taking part in this clinical trial.

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