Results of the Phase 1 Trial of RG7112, a Small-Molecule MDM2 Antagonist, in Acute Leukemia

Abstract 675 Background: Activation of the p53 pathway by inhibition of its negative regulator MDM2 has been proposed as a novel strategy for cancer therapy. We report the final results of the Phase 1 leukemia trial of RG7112, a small molecule antagonist of MDM2 which activates p53 by disrupting the p53-MDM2 interaction. Methods: The trial was designed as a multi-center, open-label Phase 1 MAD study of patients with relapsed/refractory leukemia treated with escalating doses of single agent RG7112 in two strata: A:AML, ALL, CML-BC; and B:CLL and S-CLL. RG7112 was administered orally daily for 10 days followed by 18 days of rest. Primary objectives were to determine MTD and DLT; secondary objectives to assess PK, PD and clinical responses. Enrollment is complete. 4 patients remain on study, and final data is being compiled. Peripheral blood was collected for PK and biomarkers pre-treatment, at multiple time points during the first 48 hours, and on d10. Bone marrow was collected pre-treatment, d10 and d28. Blood and marrow were purified by MACS sorting (CD19, 33 or 34 Ab). AmpliChip analysis of p53 mutational status (single nucleotide alterations exons 2–11) was performed. MIC-1 (macrophage inhibitory cytokine-1), a p53 transcriptional target, was analyzed in serum by ELISA as a pharmacodynamic marker of p53 activation. Baseline MDM2 mRNA levels, and changes from baseline, as a marker of p53 activation and feedback on MDM2, were measured by RT-PCR. A panel of 24 genes was assessed serially by TLDA (q-PCR). Results: 116 patients (84 AML,10 ALL, 2 CML, 20 CLL/sCLL) were treated with RG7112 doses ranging from 20 – 2430 (1215 BID) mg/m2/day × 10 days. The dose-exposure relationship (Cmax, AUC, and Ctrough) was approximately linear with a median half-life of 1–1.5 days. 43 patients with acute leukemia were dosed at the MTD of 1500 mg BID (flat dose) × 10 days. Major adverse events(> 20%) were nausea, diarrhea and vomiting. Other major (>10%) AEs were complications of leukemia (e.g. neutropenic fever). Clinical activity was noted during dose escalation (ASH 2011), including apoptosis in AML and CLL, CR in an AML patient (360mg/m2) stable for 6 cycles (10 months) and one patient with CLL/Richter's transformation with stable disease (40 mg/m2) for >25 cycles. New data focuses on AML patients treated at MTD. This cohort received a median of 3 prior treatments, 16 were refractory to last treatment. 17 (40%) had evidence of hematologic improvement (greater than 50% drop in peripheral and/or BM blasts by d28). Of the 31 patients who completed cycle 1 dosing, 5 patients (16%) had a CR (2 CR, 2 CRi. 1 CR without recovery). Two CR patients have proceeded to allotransplant. All CR patients' blasts were p53wt. Of the 12 additional patients with single-agent hematologic activity, 3 had biochemical evidence of tumor lysis syndrome, 10 had p53status evaluable, and mutations were detected in 3: (exon 7 missense, exon 9 frameshift, intron 7 splice). p53 activation by RG7112 was demonstrated by MIC-1 induction in serum. MIC-1 levels were elevated at RG7112 plasma concentrations >2 μg/mL or AUC24h >50 μg · h/mL and were highly correlated (0.5629) with exposure to RG7112 (AUC24h) at steady state following a sigmoidal Emax model. Preliminary data review suggests a positive correlation between exposure to RG7112 and changes in MDM2 gene expression at day 2. In addition, q-PCR analysis demonstrated exposure-dependent induction of key p53 transcriptional targets including MDM2, p21, and PUMA. p53 protein increase by WB was demonstrated at the MTD in selected patients. These findings are consistent with the proposed mechanism of action of RG7112. Conclusions: We report evidence of single agent clinical activity in patients with leukemia treated with RG7112, including 6 AML patients with CR, 5 of 31 (16%) at the MTD, and additional patients with significant decreases in blasts. Concentration-related pharmacodynamic biomarker activity of the p53 pathway was demonstrated by increases in MIC-1 levels, and induction of p53 target genes including mdm2, p21 and PUMA. 4 patients remain on treatment and final results will be reported. We provide proof of mechanism and evidence for single-agent clinical activity of MDM2 antagonism in leukemia by demonstrating complete remission, lysis of leukemic blasts and activation of p53 pathway targets in leukemic cells from patients treated with RG7112. Clinical studies of RG7112 in combination are underway. Disclosures: Andreeff: Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other. Yee: Roche: Membership on an entity's Board of Directors or advisory committees. Assouline: Roche: travel funding Other. Martinelli: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Ariad: Consultancy. Drummond: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Geho: Roche: Employment. Blotner: Roche: Employment. Cheng: Roche: Employment. Vassilev: Roche: Employment. Ding: Roche: Employment. Zhi: Roche: Employment. Middleton: Roche: Employment. Nichols: Roche: Employment.