First-in-human (FIH) phase I dose escalation study (part A) of the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) roginolisib in patients with advanced cancer and dose confirmation in uveal melanoma (part B).
Bibliographic record
Abstract
3110 Background: The highly selective oral allosteric modulator of PI3Kδ, roginolisib (IOA-244), blocks the activity of PI3Kδ -dependent signalling, in both tumour cells and Tregs. Methods: Part A explored the continuous daily dosing of roginolisib at 10, 20, 40 and 80 mg in patients (pts) with solid tumours and Follicular Lymphoma (FL). Part B consists of dose confirmation cohorts, including uveal melanoma (UM) pts. Primary objective: safety of the anticipated biologically effective dose (BED), or the recommended phase 2 dose (RP2D). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); RECIST 1.1. or Lugano-based responses; PFS and OS. Exploratory studies: phenotypic changes in circulating immune cells by Cytometry by Time of Flight (CyTOF); response assessments by radiomics; analysis of circulating protein signatures via Olink proteomic. Results: Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts, each with 4 pts. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Only Grade 1 and 2 AEs by CTCAE v5 were observed, including 2 cases of transient (lasting < 24 hrs) diarrhoea and 2 of AST/ALT elevation. Part A FL Cohort (completed): 8 pts were treated at 20 mg (n=4) and 80 mg (n=4). Grade 3 toxicities were transient and observed in 2/8 (25%) pts. 2/4 pts (50%) at the 80 mg had PR as per Lugano criteria. Neither in the solid tumour nor in the haematology pts treatment-emergent adverse events (TEAE) led to study drug discontinuation, immune related toxicity, or a Dose Limiting Toxicity. Subgroup evaluation: UM pts (Part A and Part B): 24 pts (Part A: 9 pts; Part B ongoing: 15 pts), of which 18 pts treated at 80 mg QD (RP2D). Mean time on treatment: 8.6 mo (range: 1.0-27.9 mo). ORR (RECIST 1.1): PR: 1/20 (5%); SD: 16/20 (80%). Median OS for Part A: 20.8 mo (5/9 with 4 pts alive); Part B: not determined; 1-year OS rate: Part A 66.7%; Part B: ongoing. Exploratory Investigations: Radiomics-based evaluation of CT images in pts with solid tumors assessed each metastatic organ, detecting mixed responses; peripheral proteomic evaluation detected changes in several cytokines and chemokines; CyTOF detected reduction in circulating Tregs associated with increased activated effector CD8+ T cells. Conclusions: Roginolisib is well tolerated at the 80 mg dose, shows signs of efficacy and induces phenotypic changes in the circulating immune cells. As best response at the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and UM pts (5% PR; 80% SD). Clinical trial information: NCT04328844 .
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".