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PDF file - 22K, Supplemental Fig. S3. Effect of cytoplasmic MET immunohistochemistry (IHC) staining on objective response rate in patients treated with panitumumab (pmab) plus rilotumumab (AMG 102) versus pmab plus placebo.

PDF file - 37K, Supplemental Fig. S4. The effect of baseline IGF and IGF-related protein expression on overall survival.

PDF file - 76K, Supplemental Fig. S1. (A) Randomized phase Ib/II trial of panitumumab plus rilotumumab (AMG 102) or ganitumab (AMG 479). (B) CONSORT diagram for part 2. *Panitumumab 6 mg/kg; rilotumumab 10 mg/kg with dose de-escalation to 5 mg/kg as necessary. �Panitumumab 6 mg/kg; rilotumumab 10 mg/kg; ganitumab 12 mg/kg. �Rilotumumab 10 mg/kg; ganitumab 12 mg/kg.

PDF file - 38K, Supplemental Fig. S5. The effect of baseline IGF and IGF-related protein expression on objective response rate.

PDF file - 38K, Supplemental Fig. S2. Best percent change of the sum of longest diameters of target lesions from baseline to post-baseline. (A) Panitumumab plus rilotumumab.(B) Panitumumab plus ganitumab. (C) Panitumumab alone.

Purpose: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC.Experimental Design: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work.Results: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints.Conclusions: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. Clin Cancer Res; 20(16); 4240–50. ©2014 AACR.

PDF file - 86K

Heat shock protein 90 (HSP90) is a molecular chaperone that regulates the functional stability of client oncoproteins, which is driven by the binding and hydrolysis of ATP. The geldanamycin analog, 17-AAG, binds to the ATP pocket of HSP90 leading to the degradation of client proteins such as Akt, p53, STAT3, Bcr-Abl, and Pim-1. Pim (Pim-1, -2, -3) kinases are constitutively active serine/threonine kinases overexpressed in hematological malignancies such as chronic lymphocytic leukemia (CLL). Pim kinases have several substrates which are involved in gene transcription, protein translation, cell proliferation, and apoptosis. AZD1208 is a small molecule Pim kinase inhibitor currently in clinical trials. The PI3K-dependent activation of AKT (a client protein of HSP90) and the JAK/STAT-dependent induction of PIM are partially overlapping kinase pathways. Therefore, we hypothesized that the mechanism-based combination of 17-AAG (to decrease AKT levels) with AZD1208 (to inhibit Pim kinases) will result in an increase in cytotoxicity in CLL cells. An AZD1208 dose-response experiment was performed in 4 CLL patient samples to determine the optimal cytotoxic concentrations. AZD1208 concentrations of 3 μM and 10 μM were selected to treat 22 additional CLL patient samples for 24 hours. Cell death ranged from 0-30% and 2-45%, respectively, as determined by Annexin-V/PI staining after subtraction of endogenous cell death. All CLL patient samples were sensitive to AZD1208 regardless of their prognostic markers such as IgVH mutation and ZAP70 positivity or cytogenetics such as 17p del (p53 locus) or 11q del (ATM locus). Similarly, prior treatment history or Rai stage did not influence the biological response of AZD1208 in CLL cells. Based on published data, 0.5 μM and 2 μM 17-AAG were selected for the combination treatments with AZD1208 for 24 and 48 hours. Cytotoxicity for these combinations was assessed in 13 CLL blood samples, resulting in additive (n=8) or more than additive (n=3) cell death when using the fractional two-drug combination analysis. Immunoblot analysis was performed in 3 CLL samples probing for HSP90, HSP70, Akt, Pim-1, Mcl-1, Bcl-2, Phospho-4E-BP1 (Thr37/46), 4E-BP1, and β-actin. In agreement with previous work, 17-AAG treatment resulted in an increase of HSP90 and HSP70 protein levels while Akt levels were markedly decreased. In these preliminary immunoblots, Pim-1 and Bcl-2 levels remained unchanged; however, Mcl-1 protein levels decreased in the combination treatments at 24 and 48 hours. Levels for total and phospho-4E-BP1 also declined. Taken together, these preliminary data indicate that AZD1208 (at 3 and 10 μM) has a modest cytotoxic effect in CLL cells. However, when combined with 17-AAG for 24 and 48 hours there was an additive or more than additive effect in majority of CLL samples, with the possible mechanisms of action being through the Akt and 4E-BP1 pathways. Citation Format: Fabiola Gomez, Lisa Chen, William Wierda, Varsha Gandhi. In vitro effect of AZD1208 (Pim Kinase Inhibitor) and 17-AAG (HSP90 Inhibitor) combination in CLL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2057. doi:10.1158/1538-7445.AM2013-2057