Abstract LB-214: Interim results from a randomized Phase 1-2 first-in-human (FIH) study of PK/PD guided escalating doses of SGI-110, a novel subcutaneous (SQ) second generation hypomethylating agent (HMA) in relapsed/refractory MDS and AML
Bibliographic record
Abstract
Abstract SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE's were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214
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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 | 0.005 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.005 | 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".