Phase 1b Study Of The mdm2 Antagonist rg7112 In Combination With 2 Doses/Schedules Of Cytarabine Karen Yee, md

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

Karen Yee, MD1*, Giovanni Martinelli, MD2, Sarit Assouline3, Margaret Kasner, MD4, Norbert Vey, MD PhD5*, Kevin R. Kelly, MD, PhD6, Mark W. Drummond, PhD, FRCPath, MB, CHB7, Michael Dennis, FRCP, FRCPath8*, Karen Seiter, MD9, Steven Blotner, PhD10*, Lori Jukofsky11*, Steven Middleton, PhD12*, Jianguo Zhi, PhD13*, Gong Chen, PhD14*, Hua Zhong, PhD15* and Gwen Nichols, MD13

1Princess Margaret Hospital, Toronto, ON, Canada; 2Department of Hematology and Oncological Sciences “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy; 3Jewish General Hospital, Montreal, QC, Canada; 4Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA; 5Hematology department, Institut Paoli Calmettes, Marseille, France;6University of Texas Health Science Center at San Antonio, CTRC Institute for Drug Development, San Antonio, TX; 7Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom8Haematology, Christie NHS Foundation Trust, Manchester, United Kingdom; 9New York Medical College, Valhalla, NY; 10Biostatistics, Hoffmann-LaRoche, Inc, Nutley, NJ;11Hoffmann-LaRoche, Nutley, NJ; 12Research and Early Development, Hoffmann-LaRoche, Inc, Nutley, NJ; 13Research and Early Development, Hoffmann-LaRoche, Nutley, NJ;14Bioinformatics, Hoffmann-La Roche, Nutley, NJ; 15Bioinformatics, Hoffman-La Roche, Nutley, NJ

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).

Evaluable patient characteristics by response to treatment

Arm A (N = 14)*

Best response

 3 CR

0 PR


8 PD

TP53 status

All WT


All WT

3 mutant, 5 WT

Cytogenetics (responders)

2 nl, 1 complex









Arm B (N = 23)*

Best Response

2 CR, 1 CRi, 1 CRp

1 PR

(extramedullary relapse)


11 PD

(after 1-2 cycles)

TP53 status

All WT


1 mutant

1 mutant, 10 WT

Cytogenetics (responders)

2 nl, 1 complex, 1 unknown prior MDS, 1 del 7

1 nl








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.

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