First-in-human phase I study of the bifunctional EGFR/TGF<b>β</b> fusion protein BCA101 in patients with EGFR-driven advanced solid cancers.
Bibliographic record
Abstract
3074 Background: Therapeutic targeting of EGFR has demonstrated efficacy in common advanced malignancies such as colorectal cancer (CRC), squamous cell of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). TGFβ has pro-tumorigenic effects on migration, invasion and tumor-specific immunosuppression, which may enhance the oncogenic effects of activated EGFR. Inhibition of EGFR signaling can lead to TGFβ upregulation as a resistance mechanism. BCA101 is a bifunctional recombinant fusion protein consisting of a chimeric anti-EGFR antibody and an extracellular domain (ECD) of human TGFβRII which demonstrated anti-tumor activity in several preclinical models. Methods: Patients with EGFR-driven advanced solid cancers refractory to standard therapies received BCA101 at escalating doses from 64 mg to 1000 mg intravenously (IV) weekly across 6 dose levels using a 3+3 design to determine dose limiting toxicities (DLT, established within 21 days of initial dosing), maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints include detailed pharmacokinetic (PK), pharmacodynamic (PD) studies in serial tumor and/or blood samples and assessment of anti-tumor activity. Results: As of 2/11/2021, 21 patients received single agent BCA101 at 64 (n = 3), 240 (n = 7), 500 (n = 2), 750 (n = 3), 800 (n = 3) or 1000 (n = 3) mg IV weekly, including patients with CRC (n = 6), SCCHN (n = 5) uveal melanoma (n = 2), ovarian cancer (n = 2), glioblastoma multiforme (n = 2), conjunctival melanoma, chordoma, pancreatic cancer and anal squamous cell carcinoma (all n = 1). These patients had 1-7 prior lines of antineoplastic therapy (median 4), including 3 patients with prior EGFR inhibitor exposure. Adverse events (AE) related to BCA101 observed in > 1 patient included grade (G) 1-2 rash (n = 9), G 1-2 lipase elevation (n = 2). G3 vitreous hemorrhage at the 240 mg dose level has been the only DLT. The MTD has not been reached and the RD will be based on safety, exposure and pending PD data. Saturation of the clearance was observed at doses above 500mg. Dose proportional increase in Cmax and AUC were observed with doses of 750-1000mg. Best RECISTv1.1 response was stable disease (SD) in 3/10 evaluable patients, with 1 patient on drug ≥4 months. Conclusions: BCA101 is well tolerated at biologically active doses. BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma. Clinical trial information: NCT04429542.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".