Phase I dose-escalation trial of AMXT 1501 dicaprate plus difluoromethylornithine: a dual-agent approach targeting immunosuppressive polyamine metabolism
Bibliographic record
Abstract
BACKGROUND: Dysregulation of polyamine synthesis has been observed in various cancer cell types. A novel approach to depriving cancer cells of polyamines involves the use of difluoromethylornithine (DFMO) to block polyamine biosynthesis in combination with AMXT 1501, a potent inhibitor of polyamine transport. Preclinical mouse tumor models showed that the combination of AMXT 1501 plus DFMO had strong antitumor activity, together with evidence of a stimulated immune response against tumors. MATERIALS AND METHODS: This was a multicenter phase I, open-label, two-part dose-escalation study, with expansion, to evaluate the safety and preliminary efficacy of oral AMXT 1501 in combination with oral DFMO in patients with advanced solid tumors. In part 1, patients were treated with ascending doses of AMXT 1501 alone for 2 weeks and then in combination with DFMO for an additional 2 weeks. In part 2, AMXT 1501 was dosed with escalating DFMO doses to determine the recommended phase II dose (RP2D), with an expansion cohort to confirm the RP2D. Patients with unresectable, locally advanced, or metastatic solid tumors for which no standard therapy was recognized were eligible. RESULTS: A total of 56 patients were enrolled and treated (20, 22, and 14 in part 1, part 2, and expansion, respectively). Patients were heavily pretreated; the median number of prior cancer treatments was 10.0. The most common treatment-emergent adverse events (TEAEs) were diarrhea (39.3%), nausea (37.5%), and vomiting (33.9%). There were no grade 4 or 5 TEAEs and no deaths due to TEAEs. Moderate antitumor activity was observed with 2 patients with confirmed responses and 16 patients with stable disease for an overall response rate of 6% and a clinical benefit rate of 49%. CONCLUSIONS: Overall, AMXT 1501 in combination with DFMO was safe and tolerated with evidence of preliminary clinical activity. The RP2D was determined to be AMXT 1501 600 mg twice daily plus DFMO 500 mg. CLINICAL TRIAL IDENTIFICATION: NCT03536728.
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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 | 0.000 | 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) | 0.002 | 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".