Phase 1/1b Study of RG7388, a Potent MDM2 Antagonist, in Acute Myelogenous Leukemia (AML) Patients (Pts)
Authors: Yee Karen , Martinelli Giovanni , Vey Norbert , Dickinson Michael J. , Seiter Karen , Assouline Sarit , Drummond Mark , Yoon Sung-Soo , Kasner Margaret , Lee Je-Hwan , Kelly Kevin R. , Blotner Steven , Higgins Brian , Middleton Steven , Nichols Gwen , Chen Gong , Zhong Hua , Pierceall William E. , Zhi Jianguo , Chen Lin-Chi 
Published: October 2019

Abstract
Background: RG7388 is a new, potent, oral, nutlin-class MDM2 antagonist. This trial evaluated its use in AML to determine the recommended phase 2 dose (RP2D), dose-limiting toxicities (DLTs), pharmacokinetics (PK), pharmacodynamics and clinical responses.
Methods: This multicenter, open-label phase 1/1b dose escalation (DE) study evaluated RG7388 as monotherapy (daily ´ 5 d q28d) (Part 1 DE) and in combination with cytarabine (ara-C 1 g/m2 IV x 6 d q28d) (Part 2 DE). Extensions (Ex) were initiated at the RP2D. Part 1Ex (RG7388) included pts > 70 y or > 60 y with comorbidities. Part 2Ex pts (RG7388 ± ara-C) had relapsed/refractory (R/R) AML, ≤ 2 regimens and no antecedent hematologic disorders (AHD) or transplant (ASCT). Blood and marrow analyses included PK, TP53 mutations (mt) by AmpliChip, serum MIC-1 and MDM2gene expression.
Results: To date, 86 pts have been treated. DE is complete, Part 1Ex was discontinued after 9 pts and 34 of 40 planned pts are enrolled in Part 2Ex. One DLT of prolonged myelosuppression was reported. RP2D is 1200 mg/d (600 mg bid) x 5 d q28d for both mono- and combination therapy due to diarrhea not formally a DLT but felt to be dose-limiting. The most common adverse events were GI (diarrhea reported by > 85% of pts) or infection-related (> 70% of pts).
Twenty pts received monotherapy during Part 1 DE at 400 (n = 2), 800 (n = 6) and 1600 mg (n = 12) daily x 5 d. Median age was 68.5 y (range 28-83 y), median prior therapies = 2 (range 0-4), 1 pt had ASCT and 8 had AHD. Four pts died in the first 30 days. Five pts achieved either a CR (n = 2) or CRi/MLFS (n = 3).
In Part 1Ex, 9 pts were treated with RG7388 at the RP2D. Median age was 75 y (range 66-83), 8 pts had AHD (6 prior hypomethylators, 3 pts lower intensity therapy) and 1 had prior solid tumor. Best responses reported were 1 CRi/MLFS, 1 PR, 1HI, 3 PD. Three pts died in the first 30 days. Further enrollment in this arm was discontinued as induction of prolonged myelosuppression increased the risks of infection and early deaths. Combination treatment with lower RG7388 doses may be better tolerated in this fragile elderly population.
Twenty-three pts were enrolled in Part 2 DE (RG7388 + ara-C) at daily doses of 400 (n = 10), 800 (n = 7), and 1200 mg (n = 6); median age 64 y (range 32-76); median prior therapies = 1.5 (range 0-5); prior ASCT 2; AHD 4; 5 had prior malignancies. Four pts died in the first 30 days. Six relapsed AML pts achieved CRs (4 received prior ara-C and 2 had prior hypomethylators).
To date, 34 of 40 planned pts with R/R AML have been enrolled to Part 2Ex (RG7388 ± ara-C); 23 pts have responses reported, with 4 CRs, 1 CRi, 1 PR, 1 HI, 16 PD. Three pts died in the first 30 days.
T1/2 is ≈ 1 d, irrespective of age, concomitant azoles or ara-C. Bone marrow levels are ≈ 70% of plasma drug levels at steady state.
CRs were seen in diverse pts, including varied risk groups, prior AHD, therapy-related AML (t-AML), p53 mt, R/R and de novo AML. All pts who achieved a CR during DE were relapse free for > 60 d. One pt on monotherapy and 2 on combination therapy remained relapse free for > 400 d and > 200 d from start of study, respectively. A potential predictive gene expression signature correlated with RG7388 therapy (AUC = 0.73, p = 0.021).
Conclusions: We report the Ph1/1b PK, safety and clinical activity of a new, potent MDM2 antagonist in AML. CRs occur rapidly and are durable (> 60 d) in elderly AML pts with RG7388 monotherapy and in R/R pts with combination therapy.
Table Patient characteristics by response to treatment Part 1 DE (N = 20) 16 responses Best response 2 CR; 3CRi/MLFS 3 PR 4 HI 4 PD TP53 status WT WT 1 MT, 3 WT 1 V ELN* AHD(responders) 4 I, 1 A 3 (MDS, MF, CMML) 3 I 2 (MDS, CMML) Part 1Ex (N = 9) 6 responses Best response 1 CRi/MLFS 0 PR 2 HI 3 PD TP53 status WT WT, MT 2 WT, 1 U ELN* AHD(responders) I ET Part 2 DE (N = 23) 20 responses Best response 6 CR 2 PR 2 HI 10 PD TP53 status 1 MT WT WT 1 MT, 1 V ELN* AHD(responders) 1 F, 3 I, 2 A 1 t-AML 1 I, 1 A Part 2Ex (N = 34) 23 responses Best response 4 CR; 1 CRi/MLFS 1 PR 1 HI 16 PD TP53 status 4 WT, 1 U WT WT 1 MT, 5 WT, 10 U ELN*(responders) 1 F, 3 I, 1 A A CR, complete remission; CRi, complete remission with incomplete recovery; HI, hematologic improvement; MLFS, morphologic leukemia-free state; PD, progressive disease; PR, partial response; WT, wild type; V, splice variant; U, unknown/pending; AHD, includes myelodysplastic syndrome (MDS), essential thrombocythemia (ET), chronic myelomonocytic leukemia (CMML), myelofibrosis(MF) *ELN: Risk by European Leukemia Net: favorable (F), Intermediate I and II (I), or adverse (A)

Disclosures
Yee: Roche: Research Funding. Martinelli:Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau. Vey:Roche: Honoraria. Assouline:Roche: Honoraria, Research Funding; Janssen: Honoraria. Drummond:Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Blotner:Roche: Employment. Higgins:Roche: Employment. Middleton:Roche: Employment. Nichols:Roche: Employment. Chen:Roche: Employment. Zhong:Roche: Employment. Pierceall:Roche: Employment. Zhi:Roche: Employment. Chen:Roche: Employment.