Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.
Bibliographic record
Abstract
TPS3167 Background: Protein arginine methyltransferase 5 (PRMT5) is an emerging target for cancer treatment. MTAP homozygous deletion occurs in 15% of cancers and often coincides with deletion of the tumor suppressor gene CDKN2A, leading to buildup of its substrate MTA. MTA shares close structural similarity to S-adenosyl methionine (SAM), the substrate methyl donor for PRMT5. By competing with SAM, MTA partially inhibits PRMT5. Thus, MTAP-null cancers are susceptible to further PRMT5 inhibition (Kryukov Science 2016). Current direct/indirect PRMT5 inhibitors (PRMT5i) showed preliminary anticancer activity, albeit with considerable toxicities due to their indiscriminate activities. AMG 193 is an MTA-cooperative PRMT5i that preferentially targets the MTA-bound state of PRMT5 that is enriched in MTAP-null tumors and represents a novel strategy to increase the therapeutic margin of this class of inhibitors. AMG 193 potently inhibits MTAP-null cancer cell lines and patient-derived xenografts. Methods: NCT05094336 is a first-in-human (FIH), multicenter, open-label, phase 1/1b/2 trial evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of AMG 193 in patients with advanced MTAP-null solid tumors. Eligible patients (≥ 18 years) with histologically confirmed locally advanced/metastatic solid tumors not amenable to curative treatment with surgery and/or radiation, homozygous MTAP and/or CDKN2A deletion (by local next generation sequencing), or MTAP protein loss in tumors (by central immunohistochemistry), measurable disease, ECOG PS 0‒1, adequate hematopoietic, renal, liver, pulmonary, cardiac, coagulation function and glucose control will be included. The study will be conducted in 3 parts, each with subparts. Here, we describe Part 1a/b (dose exploration). Five dose levels are planned. Treatment continues until progression or withdrawal. The primary objectives are to evaluate the safety and tolerability of AMG 193 monotherapy; endpoints include dose-limiting toxicities, treatment-emergent adverse events, serious adverse events, electrocardiograms, laboratory abnormalities, and vital signs. Secondary objectives include the characterization of the PK parameters of AMG 193 including C max , T max , and AUC after single or multiple doses. This study is expected to enroll approximately 30 patients in Part 1a/b. This is the first FIH trial open for enrollment for this new class of PRMT5i and enrollment is ongoing. Clinical trial information: NCT05094336.
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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 | 0.002 | 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 | 0.001 |
| 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".