Phase 1b Study Of The MDM2 Antagonist RG7112 In Combination With 2 Doses/Schedules Of Cytarabine

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 MDM2 gene 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][1] 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%. View this table: Evaluable patient characteristics by response to treatment 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][1] 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. [1]: #T1