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
Bibliographic record
Abstract
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 References 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 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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".