A Multi-Center, Open-Label, Phase I Study of Single Agent RG7112, A First In Class p53-MDM2 Antagonist, In Patients with Relapsed/Refractory Acute Myeloid and Lymphoid Leukemias (AML/ALL) and Refractory Chronic Lymphocytic Leukemia/Small Cell Lymphocytic Lymphomas (CLL/SCLL)

Tumor suppressor p53 is a powerful growth suppressive and pro-apoptotic molecule frequently inactivated in cancer by gene mutations or defective signaling. TP53 mutations are rare in hematopoietic malignancies but activity of wild-type p53 is frequently blunted by ATM inactivation, CDKN2A (INK4A–ARF) deletion, or over-expression of MDM2. Activation of p53 by antagonism of its negative regulator MDM2 has been proposed as a novel strategy for cancer therapy. Small-molecule MDM2 antagonists, the Nutlins (Vassilev et al. Science, 2004), have been used to validate this concept preclinically in solid tumors (Tovar et al., 2006) and acute/chronic leukemias/lymphomas (Kojima et al, 2005 and 2006, Rassidakis et al). RG7112 is a member of the Nutlin family of MDM2 antagonists with identical mechanism-of-action as nutlin-3 but improved potency and pharmacological properties.

Patients with relapsed/refractory leukemia who had adequate organ function were eligible. RG7112 was administered orally every day for 10 days followed by 18 days of rest. Primary objectives were to determine MTD and DLT, secondary PK, PD and clinical responses. Stratum A included AML, ALL, BC CML; stratum B included CLL and SLL. Cohorts of 3 patients at each dose level were escalated separately on the 2 strata. Dose escalation and de-escalation was based on NCI-CTCAE version 3.0 toxicity grades.

To date, 47 patients (27 AML, 3 ALL, 1 CML-BC, 13 CLL, 2 SLL, 1 T-PLL) have been treated with RG7112. Starting dose was 20 mg/m²/day, present dose is 810 mg/m²/day for stratum A and 1920 mg/m²/day for stratum B, with continuing escalation. Ten patients experienced moderate to severe nausea and/or vomiting, requiring anti-emetics, with 3 requiring dose modification or discontinuation. One patient had Grade 3 hyponatremia. Pharmacokinetic (PK) data demonstrate an approximate linear increase in plasma drug exposure with dose, despite PK variability. Peak concentration occurred 3–6 hours post dose with a half-life >24 hours. The p53 transcriptional target and secreted protein, MIC-1 (macrophage inhibitory cytokine-1), was evaluated as a pharmacodynamic marker of p53 activation (Yang et al., 2003). An increase in serum MIC-1 was seen at RG7112 concentrations of >1 μg/mL. Stabilization of p53 protein and induction of other p53 target genes was also observed, including CDKN1A/P21, BAX, NOXA, PUMA, FAS. Starting at 360 mg/m², evidence of clinical activity has been observed: one patient with relapsed AML achieved complete remission (CR) that is ongoing for more than 9 months and decreased WBC and apoptosis induction were seen in CLL/SLL patients. Enrollment is ongoing and will be updated.

We here report the first clinical trial of an MDM2 antagonist, RG7112. The molecule is well tolerated with continuing dose escalation. We provide proof-of-principle by demonstrating p53 stabilization, activation of p53 targets and the p53 pathway. One CR has been observed in AML and reductions in lymph node/spleen size and circulating leukemia cells in CLL/SLL. Future single agent and combination studies of RG7112 in leukemias are warranted.

Andreeff:Roche: Research Funding. Padmanabhan:Roche: Research Funding. Strair:Roche: Research Funding. Kirschbaum:Roche: Research Funding. Maslak:Roche: Research Funding. Hillmen:Roche: Research Funding. Vassilev:Roche: Employment. Nichols:Roche: Employment.