Lori Jukofsky

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.

Purpose: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted. Experimental Design: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. Results: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. Conclusions: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies. Clin Cancer Res; 22(4); 868–76. ©2015 AACR.

Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma

BACKGROUND & AIMS Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. METHODS Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. RESULTS 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. CONCLUSIONS Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. LAY SUMMARY Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. CLINICAL TRIAL REGISTRATION This trial is registered at Clinicaltrials.gov (NCT01507168).

Acute myeloid leukemia patients' clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts.

In translational research described, we investigated biomarker expression by flow cytometry for MDM2 antagonist clinical response association in relapsed/refractory AML patients treated with idasanutlin-based therapy ( [Clinicaltrials.gov][1] identifier: [NCT01773408][2] ). As MDM2 targets p53 for

MDM2 antagonist clinical response association with a gene expression signature in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is uniquely sensitive to p53 activation 1, 2 as ≈90% of patients carry wild-type TP53 and frequent MDM2 overexpression.3 MDM2 blocks p53 transactivation and targets p53 for ubiquitin-dependent degradation.4, 5 Nutlins have been characterized as potent and selective small-molecule MDM2 antagonists.1, 6–8 RG7112 was the first such MDM2 antagonist to undergo clinical assessment in solid tumors and leukaemia trials.1, 2, 9 As not all patients with functional p53 will respond to MDM2 antagonists, diagnostic tools may identify patients likely to respond.

Combining expression of GPC3 in tumors and CD16 on NK cells from peripheral blood to identify patients responding to codrituzumab

Background Codrituzumab, a monoclonal antibody targeting an oncofetal protein glypican-3 (GPC3) expressed on cell surface of hepatocellular carcinoma (HCC) induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits tumor growth in preclinical studies. Based on this mechanism, tumor GPC3 expression and CD16 expression on NK cells, which are the effector cells of ADCC, were investigated to correlate with codrituzumabs clinical efficacy in patients with advanced HCC. Results Joint analyses of the two biomarkers revealed that both high levels of GPC3 and CD16 were required for patients to benefit from codrituzumab; lack of either one of them would lead to a loss of the therapeutic effect. Conclusions These results suggest the combination of tumor GPC3 expression and CD16 expression on NK cells from peripheral blood at baseline as a composite biomarker to select HCC patients for codrituzumab. Impact The conclusion warrants a future study in an HCC population with both high GPC3 expression and high levels of CD16 at baseline to establish codrituzumabs therapeutic benefit in HCC. Methods Data from a phase II clinical trial of codrituzumab were used for the analyses. GPC3 expression in baseline tumor biopsies was determined by immunohistochemistry (IHC) analysis, and baseline CD16 expression on NK cells were quantified by peripheral blood lymphocyte immunophenotyping. According to high or low expression of GPC3 and CD16, different patient subgroups were formed; for each subgroup, overall survival of patients having high codrituzumab exposure was compared to that of patients receiving placebo.

Abstract 3944: Combining tumor glypican-3 expression and CD16 Expression on NK cells from peripheral blood to identify patients responding to codrituzumab/GC33/RO5137382

Background & Aims: Codrituzumab (GC33 or RO5137382), a monoclonal antibody targeting an oncofetal protein glypican-3 (GPC3) expressed on the cell surface of hepatocellular carcinoma (HCC), induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits tumor growth in preclinical studies. Based on this mechanism of codrituzumab, two biomarkers GPC3 and CD16 of the NK cells, which are the effector cells of ADCC, were investigated to correlate with clinical efficacy of codrituzumab in patients with advanced HCC. Methods: Data from a phase II clinical trial of codrituzumab were used for this analysis. GPC3 expression was determined by immunohistochemistry (IHC) analysis of tumor biopsies, and CD16 expression on NK cells were quantified by a flow cytometry analysis of peripheral blood mononuclear cells. Overall survival of patients with high exposure of codrituzumab or placebo (n = 113) was used to compare different patient subgroups stratified by high or low expression of GPC3 and CD16. Results: In individual-biomarker analyses, longer survival after codrituzumab treatment correlates with either high expression level of GPC3 in tumors (n = 97, HR = 0.39, 95%CI = 0.21 - 0.70, p = 0.00081) or a relatively high level of CD16 expressed on NK cells (n = 80, HR = 0.44, 95%CI = 0.23 - 0.83, p = 0.0056) at baseline. Furthermore, joint analyses of the two biomarkers reveal that both high levels of GPC3 and CD16 are required for patients to benefit from codrituzumab treatment (n = 67, HR = 0.29, 95%CI = 0.13 - 0.62, p = 0.00074), and lack of either one of them leads to a loss of codrituzumab therapeutic effect. Conclusions: The retrospective analysis supports the mechanism of ADCC, in which the combination of high GPC3 expression in tumors and high CD16 expression in NK cells from peripheral blood is associated with prolonged overall survival given treatment of codrituzumab. This result supports the usage of both GPC3 and CD16 as potential biomarkers to select HCC patients for codrituzumab treatment. Citation Format: Gong Chen, Ya-Chi Chen, Bernhard Reis, Anton Belousov, Lori Jukofsky, Christine Rossin, Axel Muehlig, Chao Xu, Laurent Essioux, Toshihiko Ohtomo, Laura Di Laurenzio, Oscar Puig, Ray Lee. Combining tumor glypican-3 expression and CD16 Expression on NK cells from peripheral blood to identify patients responding to codrituzumab/GC33/RO5137382. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3944.

Abstract 2835: MDM2 antagonist-based therapeutic response is discriminated by a 4-gene signature in acute myeloid leukemia patients

The activity of p53, a key tumor suppressor is tightly controlled by MDM2-mediated ubiquination and degradation. Nutlins, a class of small-molecule MDM2 antagonists, have been characterized as drivers of p53 re-activation. Acute myeloid leukemia (AML) is uniquely sensitive to p53 re-activation as ∼90% of cases have wild-type TP53 and frequent MDM2 overexpression to overcome mechanisms of oncogene addiction. Personalized theranostic strategies may distinguish patients likely to clinically benefit from MDM2-antagonist therapy. Association between MDM2 antagonist (RG7112) growth inhibition (IC50s) in 287 human cancer cell lines (Cell Lines for Oncology/Chugai Accumulative Tumor Encyclopedia), and pretreatment RNAseq profiling established a classifier comprising MDM2, XPC, BBC3, and CDKN2A. This signature significantly associated with cell-line efficacy to MDM2 antagonist (odds ratio = 2.53; P RG7112 treatment was assessed in a phase 1 dose escalation trial in relapsed/refractory AML patients (NO21279). Signature scores of AML patient blood specimens at baseline significantly associated with clinical response (PD In summary, we demonstrate that a biological classifier discriminates response broadly to MDM2-antagonist therapy. The level of evidence attained by cell line efficacy modeling and response assessments in trial NO21279 (with MDM2 antagonist RG7112) and now in trial NP28679 (with MDM2 antagonist RG7388) adds substantial weight to the validity of this panel. Citation Format: Hua Zhong, Gong Chen, Lori Jukofsky, David Geho, Sung Won Han, Fabian Birzele, Sabine Bader, Lucia Himmelein, James Cai, Zayed Albertyn, Mark Rothe, Laurent Essioux, Helmut Burtscher, Steven A. Middleton, Lin-Chi Chen, Markus Dangl, William E. Pierceall, Gwen Nichols. MDM2 antagonist-based therapeutic response is discriminated by a 4-gene signature in acute myeloid leukemia patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2015-2835