Phase 1b Study Of The MDM2 Antagonist RG7112 In Combination With 2 Doses/Schedules Of Cytarabine
Bibliographic record
Abstract
Abstract Background Activation of the p53 pathway through inhibition of its negative regulator MDM2 is a promising strategy for cancer therapy. Phase 1 results in AML with RG7112, a small-molecule antagonist of MDM2, demonstrated single-agent activity, including complete responses (CRs) (ASH 2012). Here we report results of a Phase 1b trial of RG7112 in combination with Ara-C in pts with AML. Methods This is a multicenter, open-label phase 1b study of pts with AML treated with escalating oral doses of RG7112 in 2 arms. Arm A: pts unsuitable for standard (re)induction, treated with RG7112 and Ara-C 20 mg/m2 SC both daily × 10 days every 28 days; arm B: relapsed/refractory pts treated with RG7112 × 5 days and Ara-C 1 g/m2 IV × 6 days every 28 days. Primary objectives were to determine MTD and DLTs; secondary objectives were pharmacokinetics (PK), pharmacodynamics, and clinical responses. Blood and bone marrow were collected for PK and biomarker analyses pre- and at multiple on-treatment time points. Mutations in TP53 were detected using the PCR- and microarray-based AmpliChip p53 research test, detecting single-nucleotide alterations of exons 2-11. Pharmacodynamic markers of p53 activation included serum MIC-1 measured by ELISA, and MDM2gene expression by RT-PCR. Results Enrollment is complete with forty-three pts treated (16 arm A, 27 arm B) with escalating doses of RG7112. 3 DLTs included rash and prolonged thrombocytopenia (Arm B) and diarrhea (Arm A). MTD was 1000 mg bid × 10 days (arm A) and 1500 mg bid x 5 days (arm B) based on prolonged cytopenias. PK (Cmax, AUC, and Ctrough) data were comparable with historic monotherapies, suggesting no drug-drug interactions. Adverse events (> 20%) were GI or infectious. Clinical activity Arm A: median age 70 y, median prior therapies 1. During the initial safety period 2 pts died (ARDS, sepsis). See table for results for the 14 pts completing cycle 1. CRs (21%) occurred at 1g and 2g of RG7112 in pts with no prior therapy or HU. ORR (CR,PR, SD/HI) was 43%. Arm B median age 50 y, median prior therapies 3 (all relapsed after Ara-C). During the initial safety period 4 pts died of sepsis (1 complicated by multi-organ failure). See table for results for the 23 pts completing cycle 1. CRs (17%) were observed in patients refractory to DA, and MEC (2) or HiDAc (1) and occurred at RG7112 doses >2g/d. ORR was 52%. Three pts bridged to transplant (1 CR, 2 HI). Abbreviations CRi, complete remission with incomplete recovery; CRp, complete remission with incomplete platelet recovery; PR, Partial Response; SD, Stable Disease; HI, Hematologic Improvement; HU, Hydroxyurea; PD, Progressive Disease; Nl, Normal Karyotype; DA, Daunorubicin and Ara-C; MEC, Mitoxantrone, Etoposide, and Ara-C; HiDAc, High dose intermittent Ara-C; AZA, Azacitidine; MDS, myelodysplastic syndromes. *Two continue on therapy as of July 2013 Biomarker activity MIC-1 induction was similar to RG7112 monotherapy. Preliminary data demonstrated increased MDM2 expression on day 2, consistent with the MoA (p53 activation and associated feedback) previously reported (Ray-Coquard, 2012). TP53 activation did not consistently correlate with clinical activity, implying factors downstream of functional p53 may be critical for activity. Additionally, a predictive mRNA signature that significantly correlates with RG7112 efficacy in cell lines and in phase 1 AML pt samples (Spearman correlation, 0.6; P= 0.0009; manuscript in preparation) was prospectively evaluated in this study. Conclusions Here we report the safety and clinical activity of an MDM2 antagonist in combination with Ara-C in pts with AML. CRs in elderly and heavily pretreated pts refractory to cytarabine-containing regimens were observed. Pharmacodynamic activity of the p53 pathway was demonstrated by increases in MIC-1 and MDM2 expression. Results of ongoing biomarker analyses to predict response for future development will be reported. Disclosures: Yee: Roche: Research Funding. Assouline:Roche: Research Funding. Kasner:Roche: Research Funding. Blotner:Roche: Employment. Jukofsky:Roche: Employment. Middleton:Roche: Employment. Zhi:Roche: Employment. Chen:Roche: Employment. Zhong:Roche: Employment. Nichols:Roche: Employment.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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".