750 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
Bibliographic record
Abstract
Background CFI-402411 is a potent inhibitor of HPK1 (Hematopoietic progenitor kinase 1), a protein serine/threonine kinase that negatively-regulates T-cell activation. Following T-cell receptor engagement, HPK1 phosphorylates SLP-76, to down-regulate signals required for T-cell activation and proliferation1,2. CFI-402411 is expected to relieve HPK1-mediated inhibition of T-cell activation, facilitating an anti-tumor immune response. Methods In this ongoing phase 1 study, part A evaluates CFI-402411 daily dose in dose escalation cohort (3+3 design) and dose expansion, part B evaluates CFI-402411 in combination with pembrolizumab in dose escalation (BOIN design) and dose expansion in pembrolizumab eligible tumors. Dose limiting toxicity (DLT) is any grade ≥3 toxicity in the first cycle of therapy (21d cycles). Starting dose was 80mg. Results As of 14 May 2022 (data cutoff), 25 and 9 patients (pts) enrolled to A and B respectively. Median age was 62 (30-79). Median cycles of treatment were 3 (range: 0-20). Majority of patients were male (A, 60% and B, 78%). Median prior regimens were 2 (range: A, 1-4; B, 1-3). 6pts (A, 24%) and 5pts (B, 56%) received prior anti-PD-1/anti-PD-L1 inhibitor. Diagnoses in ≥2pts for A: colorectal (6pts), pancreatic (5pts); for B: small cell lung cancer (2pts). 8 dose levels (80 to 800 mg) have been studied in A, 2 dose levels (60 and 80 mg) in B. TEAEs occurring in ≥40% of A pts: diarrhea (n=17, 68%), nausea (n=11, 44%), decreased appetite (n=10, 40%); and B: vomiting (n=4, 44%). 19pts (76%) in A and 6pts (67%) in B experienced CFI-402411 related AEs. Immune-related AEs were reported in 1pt (A; 4% [ALT and AST increase]) and 2pts (B; 22% [febrile illness, flu-like symptoms]). Grade ≥3 AEs and serious AEs occurred in 14pts (56%) and 10pts (40%) in A; and 3pts (33%) and 4pts (44%) in B. DLTs occurred in 2pts (A [800mg]: diarrhea, spinal cord compression) and 1pt (B [80mg+pembro]: flu-like symptoms). No novel toxicity signals were seen. Disease control rates were 24% in A (6/25) and 44% in B (4/9). One B patient (11%), squamous head and neck cancer (H&N) previously treated with pembrolizumab, has confirmed partial response (PR) and remains on treatment, 8 cycles. An additional H&N patient treated with monotherapy CFI-402411 achieved unconfirmed PR after data cut. Conclusions CFI-402411 is a well-tolerated, potent inhibitor of HPK1 with a manageable AE profile and initial evidence of activity. RP2D and additional safety and efficacy data will be reported at conference presentation. 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 Hu MQ. Human HPK1, a novel human hematopoietic progenitor kinase that actives the JNK/SAPK kinase cascade. Genes & Development. 1996;10:2251–2264. Lasserre RC-G. Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation. Immuno Res. 2011;295:839–853. Ethics Approval This study obtained ethics approvals at the following ethics/IRB’s; Papadopoulos, KP; Advarra IRB ID: Pro00051609 Fu, S; University of Texas MD Anderson Cancer Center Office of Human Subject Protection IRB ID 2020-0678 Hamilton, E; Advarra IRB ID: Pro00051611 Spira, A; Advarra IRB ID: Pro00043629 Laurie, S; Ontario Cancer Research Ethics Board, CTO Project ID 3320 Wang, J; Advarra IRB ID: Pro00051611 Ma, B; Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee CREC Ref. No .: 2020.367-T Spreafico, A; Ontario Cancer Research Ethics Board, CTO Project ID 3320 Sharma, M; Advarra IRB: ID Pro00051609 Chu, Q; Health Research Ethics Board of Alberta Ethics ID: HREBA.CC-20-0504_REN1 Hamid, O; WCG, IRB: IRB Tracking Number: 2020236 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 | 0.002 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.006 |
| 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".