Efficacy and Tolerability of CEP-18770 in Combination with Dexamethasone and Lenalidomide Using a SCID-Hu Model of Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2946-2946
Author(s):  
Eric Sanchez ◽  
Cydney M Nichols ◽  
Alison C Lam ◽  
Mingjie Li ◽  
Jennifer Li ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Research Funding ◽  
Tumor Volume ◽  
Single Agent ◽  
Volume Growth ◽  
Xenograft Model ◽  
Combination Regimen ◽  
Combination Therapies ◽  
Combination Regimens

Abstract Abstract 2946 Introduction: We previously demonstrated the anti-MM effects of the proteasome inhibitor (PI) CEP-18770 with lenalidomide (LEN) and/or dexamethasone (DEX) using the MM xenograft model LAGκ-1B. Bortezomib has been shown to demonstrate synergistic anti-MM effects with both of these classes of drugs which has led to the successful use of these combinations to treat patients with MM. Thus, we conducted the current study to ascertain the anti-MM effects of CEP-18770 in combination with DEX and/or LEN in vivo using a different human severe combined immunodeficient (SCID) -hu MM model (LAGκ-1A) than then one previously evaluated and mentioned above (LAGκ-1B). Methods: Each naïve SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were randomized into treatment groups based on human immunoglobulin G (IgG) levels. CEP-18770 (4 mg; Cephalon, Inc., Frazer, PA, USA) stock solution was dissolved in propylene glycol (800 μl) and added to 5% mannitol to generate a final stock solution of 1 mg/ml, diluted (5% mannitol). Mice were injected with 1 mg/kg twice weekly (T, Th) via intravenous (i.v.) injection. LEN stock solutions were prepared daily from pills and diluted in 5% carboxymethylcellulose. DEX was obtained as a 4 mg/ml stock solution, diluted (0.9% sodium chloride). Mice were treated daily with DEX at 1.25 mg/kg via intraperitoneal (i.p.) injection and 30 mg/kg of LEN via oral gavage. On a weekly basis, tumor size was measured using standard calipers (n = 9–10 mice/group) and human IgG levels with an ELISA (Bethyl Laboratories, Montgomery, TX). This study was conducted according to protocols approved by the Institutional Animal Care and Use Committee. Results: At day 35 post tumor implantation, mice receiving the doublets of CEP-18770 plus daily dexamethasone or lenalidomide and the triplicate regimen containing all three drugs markedly inhibited tumor volume growth compared to mice receiving vehicle. Notably, P -values could not be calculated because all mice receiving the doublet and triplicate combination regimens had undetectable tumor volumes (zero tumor volume measurements) and thus a t-test could not be calculated. These tumors remained undetectable beginning at day 35 and throughout the study until its termination (day 91). CEP-18770 or DEX administered alone also significantly inhibited tumor volume growth (P = 0.0005, P = 0.0205, respectively) at this same time point, when compared to mice receiving vehicle, whereas LEN alone did not. However, in contrast to the tumors which eventually grew in mice after single agent treatment with CEP-18770, DEX, or LEN and the doublet LEN + DEX group, tumors did not reappear among mice which received the CEP-18770 doublet or CEP-18770 triplicate combination regimens. Similar inhibitory effects were obtained for IgG levels as those observed for tumor volume growth inhibition. Mice receiving CEP-18770 doublets (CEP-18770 + DEX or LEN) or all three drugs together were sacrificed at day 91. Overall, 10/10 mice survived the CEP-18770 + DEX regimen, and 9/10 mice survived in both the CEP-18770 + LEN and CEP-18770 + DEX + LEN groups. Conclusions: These in vivo studies using our LAGk-1A SCID-hu model show that CEP-18770 administered alone, in combination with DEX or LEN, or in triplicate combination with both DEX and LEN, resulted in significant inhibition of tumor growth as determined by measuring tumor volume and IgG levels when compared to vehicle-treated and single agent treated mice. Although the initial anti-MM effects were similar between single agent CEP-18770 and the doublet and triplicate combination therapies, with longer follow-up the doublet and triplicate combination therapies proved to be superior. The toxicity profile was negligible and similar between CEP-18770 monotherapy, combined with either DEX or LEN, and the triplicate combination regimen. Pre and post-treatment body weight comparisons of these groups demonstrated that mice receiving the different treatments gained weight to a similar extent during study treatment. This study demonstrates that using a different MM model (LAGκ-1A), the PI CEP-18770 in combination with DEX and/or LEN results in significant tumor growth and IgG inhibition, and provides further support for the development of the novel agent for the treatment of MM. Disclosures: Berenson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding.

Efficacy and Tolerability of CEP-18770 In Combination with Dexamethasone and Lenalidomide Using a SCID-Hu Model of Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4066-4066
Author(s):  
Eric Sanchez ◽  
Mingjie Li ◽  
Cathy Wang ◽  
Zhi-Wei Li ◽  
Haiming Chen ◽  
...  
Keyword(s):  
Tumor Volume ◽  
Single Agent ◽  
Volume Growth ◽  
In Vivo Studies ◽  
Combination Regimen ◽  
The Novel ◽  
Tumor Implantation ◽  
Treatment Regimens ◽  
Time Point

Abstract Abstract 4066 Introduction: Although we have previously demonstrated the anti-myeloma (MM) effects of the novel proteasome inhibitor (PI) CEP-18770 alone and the ability of this PI to enhance the anti-MM effects of melphalan as well as another PI bortezomib (Sanchez et al. Br J Haematol, 148(4):569-581 [2010]), this novel PI has not been evaluated in combination with immunomodulatory agents (IMiDs) or glucocorticosteroids. Bortezomib has been shown to demonstrate synergistic anti-MM effects with both of these classes of drugs which have led to the successful use of these combinations to treat patients with MM. Thus, we conducted these studies to ascertain the anti-MM effects of CEP-18770 in combination with the glucocorticosteroid dexamethasone (DEX) and/or IMiD lenalidomide (LEN) in vivo using our human SCID (severe combined immunodeficient)-hu MM, LAGk-1B (bortezomib-resistant tumor). Methods: Each naïve SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were randomized into treatment groups. CEP-18770 (4 mg; Cephalon, Inc., Frazer, PA, USA) stock solution was dissolved in propylene glycol (800 μ l) and added to 5% mannitol to generate a final stock solution of 1 mg/ml, diluted (5% mannitol). Mice were injected with 3 mg/kg twice weekly (T, Th) via intravenous (i.v.) injection. LEN stock solutions were prepared daily from pills and diluted in 5% carboxymethylcellulose. Mice were treated with 30 mg/kg of this IMiD daily via oral gavage. DEX was obtained as a 4 mg/ml stock solution, diluted (0.9% sodium chloride). Mice were treated with 1.25 mg/kg daily of this glucocorticosteroid via intraperitoneal (i.p.) injection. Tumor size was measured using standard calipers on a weekly basis (n=9–10 mice/group). Results: At day 28 post-tumor implantation, mice receiving CEP-18770 plus daily DEX markedly inhibited tumor volume growth (P=0.0007), compared to mice receiving vehicle, whereas CEP-18770 alone did not show a significant effect, but by day 35 both CEP-18770 administered alone and in combination with DEX significantly inhibited tumor volume growth (P < 0.0001) compared to mice receiving vehicle. Notably, DEX alone had no anti-MM activity at any time point throughout study duration. Overall, mice survived the DEX, CEP-18770, and CEP + DEX treatment regimens well with 9/10, 10/10, and 10/10 mice alive, respectively, at study termination (day 35). Similarly, at day 28 post-tumor implantation, mice receiving CEP-18770 plus daily LEN showed markedly smaller tumors compared to mice receiving vehicle (P=0.0004), whereas CEP-18770 alone did not show an effect. However, by day 35, both CEP-18770 administered alone (P < 0.0001) and the combination of CEP-18770 + LEN (P < 0.0001) significantly inhibited tumor volume growth compared to mice receiving vehicle alone. LEN alone showed no anti-MM activity at any time point throughout the study. Overall, mice survived the CEP-18770, LEN, and CEP + LEN treatment regimens well with 10/10, 10/10, and 9/10 mice alive, respectively, at study termination (day 35). The anti-MM effects of the triplicate combination of CEP-18770 + DEX + LEN in LAGk-1B-bearing mice was also evaluated. At day 28 and day 35, the triplicate combination also produced markedly smaller tumor volumes (P=0.0001) compared to vehicle-treated mice. However, this was not significantly different from single agent CEP-18770 or the combination of this PI with DEX or LEN. Overall, mice survived the triplicate combination regimen well with 9/10 mice alive at study termination (day 35). Conclusions: These in vivo studies using our bortezomib-resistant LAGk-1B SCID-hu model show that CEP-18770 administered alone, in combination with DEX or LEN, or in triplicate combination with both DEX and LEN, resulted in statistically significant tumor volume growth inhibition when compared to vehicle-treated mice. Although initial anti-MM effects were more marked with the combination therapies, with longer follow-up single agent CEP-18770 produced similar anti-tumor effects as the CEP-18770-containing doublet and triplicate combinations. Furthermore, the toxicity profile was favorable and similar between CEP-18770 monotherapy, combined with either DEX or LEN, and the triplicate combination regimen. These results provide further support for the development of the novel PI CEP-18770 for the treatment of MM. Disclosures: Berenson: Cephalon, Inc.: Consultancy, Research Funding.

scholarly journals Targeting Antibody Checkpoint Fcgriib Using Monoclonal Antibody BI-1206 to Overcome Therapeutic Resistance in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Alexa A Jordan ◽  
Joseph McIntosh ◽  
Yang Liu ◽  
Angela Leeming ◽  
William Lee ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Publicly Traded ◽  
In Vivo Efficacy ◽  
Mantle Cell ◽  
Xenograft Models

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.

Oral Dosing of the Novel Proteasome Inhibitor CEP-18770 Shows Marked Anti-Myeloma Effects in SCID-Hu Models of Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1840-1840
Author(s):  
Eric Sanchez ◽  
Mingjie Li ◽  
Jeffrey A Steinberg ◽  
Cathy S Wang ◽  
Jing Shen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Proteasome Inhibitor ◽  
Tumor Volume ◽  
Single Agent ◽  
Volume Growth ◽  
Oral Formulation ◽  
Clinical Development ◽  
Scid Mice ◽  
Control Group ◽  
Treatment Groups

Abstract Abstract 1840 Poster Board I-866 Introduction: Currently, there is no orally administered proteasome inhibitor (PI) which has been FDA approved for the treatment of any cancer. The first PI in clinical development, bortezomib, was approved in 2003 following two successful single-agent phase II trials in relapsed multiple myeloma (MM). In contrast to bortezomib which is administered by intravenous bolus, CEP-18770 is a PI that is active as an oral formulation. Furthermore, the efficacy of orally administered CEP-18770 in multiple MM models has not been reported. In this study, we determined the effects of orally administered CEP-18770 therapy at escalating doses either daily or twice weekly in severe combined immunodeficient (SCID) mice bearing human MM that has been serially passaged in SCID mice from bone marrow derived from a MM patient before (LAGκ-1A) and after resistance (LAGκ-1B) to bortezomib developed. Materials and Methods: Each naïve SCID mouse received a 20 — 40 mm3 MM tumor piece which was surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and animals were randomized into treatment groups. CEP-18770 was administered via oral gavage either daily at 5 mg/kg or twice weekly at 10 mg/kg (M, W) throughout the study. Each week, mice were bled for hIgG levels (where applicable) and tumors were measured using standard calipers. Data graphed is the mean ± SEM with n = 15 mice/group. Results: Single-agent CEP-18770 administered orally significantly inhibited tumor growth in bortezomib-sensitive LAGκ-1A-bearing mice. A significant inhibition of both human paraprotein secretion and reduction of tumor volume was observed as soon as three weeks following initiation of treatment with CEP-18770 at 10 mg/kg twice weekly (hIgG: P = 0.0011 and tumor volume: P = 0.001). Furthermore, tumor volume growth to 700 mm3 was delayed by 94% (day 32.5 for control compared to day 63) among animals receiving this treatment regimen when compared to animals receiving no treatment. At day 35, daily administration of the PI at 5 mg/kg also resulted in significant tumor inhibition (hIgG: P < 0.0001 and tumor volume: P < 0.0001). Reductions of tumor growth by 75%, 95%, 97% and 98% on days 28, 35, 42 and 49 respectively, were observed when compared to the control group. The effect of single-agent CEP-18770 dosed orally in SCID mice bearing nonsecretory bortezomib-resistant LAGκ-1B tumors was also evaluated. Four weeks following initiation of treatment, 5 mg/kg administered daily or 10 mg/kg twice weekly, resulted in a significant reduction in tumor volume (P = 0.0327 and P = 0.0018 respectively). Tumor volume growth to 300 mm3 was delayed by 36% (day 31 for control compared to day 42 for CEP-18770-treated group) in animals receiving 5 mg/kg daily compared to animals receiving no treatment. Tumor volume at 220 mm3 was delayed by 50% (day 28 for control compared to day 42 for CEP-18770-treated mice) among animals receiving 10 mg/kg twice weekly when compared to the untreated control group. Reductions of tumor growth by 78%, 73%, 74% and 70% on days 35, 42, 49 and 56 respectively, were observed when compared to the control group. Moreover, body weights measured at treatment cessation were not significantly different between pre- and post-treatment levels for both treatment groups and MM tumor types. Conclusions: The results of these studies show a marked reduction of tumor size and delay of tumor growth, when compared to the control group, following oral administration of CEP-18770 in LAGκ-1A and LAGκ-1B-bearing mice. The potential availability of an oral PI will greatly enhance the convenience of administration of drugs in this class as bortezomib has only shown efficacy when given intravenously. Other PIs that are bioavailable and active orally in preclinical studies in the treatment of MM are now in early clinical development. The data presented in our study provide further support for clinical development of CEP-18770 as an oral formulation for the treatment of MM. Disclosures: Berenson: Cephalon, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Targeted Inhibition of PI3K α/δ Is Synergistic with BCL-2 Blockade in Genetically Defined Subtypes of DLBCL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 39-39
Author(s):  
Kamil Bojarczuk ◽  
Kirsty Wienand ◽  
Jeremy A. Ryan ◽  
Linfeng Chen ◽  
Mariana Villalobos-Ortiz ◽  
...  
Keyword(s):  
Tumor Growth ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Research Funding ◽  
Single Agent ◽  
Research Report ◽  
Genetic Bases

Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease that is transcriptionally classified into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. A subset of both GCB- and ABC-DLBCLs are dependent on B-cell receptor (BCR) signaling. Previously, we defined distinct BCR/PI3K-mediated survival pathways and subtype-specific apoptotic mechanisms in BCR-dependent DLBCLs (Cancer Cell 2013 23:826). In BCR-dependent DLBCLs with low baseline NF-κB activity (GCB tumors), targeted inhibition or genetic depletion of BCR/PI3K pathway components induced expression of the pro-apoptotic HRK protein. In BCR-dependent DLBCLs with high NF-κB activity (ABC tumors), BCR/PI3K inhibition decreased expression of the anti-apoptotic NF-κB target gene, BFL1. Our recent analyses revealed genetic bases for perturbed BCR/PI3K signaling and defined poor prognosis DLBCL subsets with discrete BCR/PI3K/TLR pathway alterations (Nat Med 2018 24:679). Cluster 3 DLBCLs (largely GCB tumors) exhibited frequent PTEN deletions/mutations and GNA13 mutations. Cluster 5 DLBCLs (largely ABC tumors) had frequent MYD88L265P and CD79B mutations that often occurred together. These DLBCL subtypes also had different genetic mechanisms for deregulated BCL2 expression - BCL2 translocations in Cluster 3 and focal (18q21.33) or arm level (18q) BCL2 copy number gains in Cluster 5. These observations prompted us to explore the activity of PI3K inhibitors and BCL2 blockade in genetically defined DLBCLs. We utilized a panel of 10 well characterized DLBCL cell line models, a subset of which exhibited hallmark genetic features of Cluster 3 and Cluster 5. We first evaluated the cytotoxic activity of isoform-specific, dual PI3Kα/δ and pan-PI3K inhibitors. In in vitro assays, the PI3Kα/δ inhibitor, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. We next assessed the transcriptional abundance of BCL2 family genes in the DLBCLs following copanlisib treatment. In BCR-dependent GCB-DLBCLs, there was highly significant induction of the pro-apoptotic HRK. In BCR-dependent ABC-DLBCLs, we observed significant down-regulation of the anti-apoptotic BFL1 protein and another NF-κB target gene, BCLxL (the anti-apoptotic partner of HRK). We then used BH3 profiling, to identify dependencies on certain BCL2 family members and to correlate these data with sensitivity to copanlisib. BCLxL dependency significantly correlated with sensitivity to copanlisib. Importantly, the BCLxL dependency was highest in DLBCL cell lines that exhibited either transcriptional up-regulation of HRK or down-regulation of BCLxL following copanlisib treatment. In all our DLBCL cell lines, PI3Kα/δ inhibition did not alter BCL2 expression. Given the genetic bases for BCL-2 deregulation in a subset of these DLBCLs, we next assessed the activity of the single-agent BCL2 inhibitor, venetoclax, in in vitro cytotoxicity assays. A subset of DLBCL cell lines was partially or completely resistant to venetoclax despite having genetic alterations of BCL2. We postulated that BCR-dependent DLBCLs with structural alterations of BCL2 might exhibit increased sensitivity to combined inhibition of PI3Kα/δ and BCL2 and assessed the cytotoxic activity of copanlisib (0-250 nM) and venetoclax (0-250 nM) in the DLBCL cell line panel. The copanlisib/venetoclax combination was highly synergistic (Chou-Talalay CI<1) in BCR-dependent DLBCL cell lines with genetic bases of BCL2 deregulation. We next assessed copanlisib and venetoclax activity in an in vivo xenograft model using a DLBCL cell line with PTENdel and BCL2 translocation (LY1). In this model, single-agent copanlisib did not delay tumor growth or improve survival. Single-agent venetoclax delayed tumor growth and improved median survival (27 vs 51 days, p<0.0001). Most notably, we found that the combination of copanlisib and venetoclax delayed tumor growth significantly longer than single-agent venetoclax (p<0.0001). Additionally, the combined therapy significantly increased survival in comparison with venetoclax alone (median survival 51 days vs not reached, p<0.0013). Taken together, these results provide in vitro and in vivo pre-clinical evidence for the rational combination of PI3Kα/δ and BCL2 blockade and set the stage for clinical evaluation of copanlisib/venetoclax therapy in patients with genetically defined relapsed/refractory DLBCL. Disclosures Letai: AbbVie: Consultancy, Other: Lab research report; Flash Therapeutics: Equity Ownership; Novartis: Consultancy, Other: Lab research report; Vivid Biosciences: Equity Ownership; AstraZeneca: Consultancy, Other: Lab research report. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.

Efficacy of adavosertib therapy against anaplastic thyroid cancer

2021 ◽  
Author(s):  
Yu-Ling Lu ◽  
Yu-Tung Huang ◽  
Ming-Hsien Wu ◽  
Ting-Chao Chou ◽  
Richard J Wong ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tumor Growth ◽  
Single Agent ◽  
Xenograft Model ◽  
Anaplastic Thyroid Cancer ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cancer Tumor

Wee1 is a kinase that regulates the G2/M progression by inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.

The Novel Proteasome Inhibitor CEP-18770 Inhibits Myeloma Tumor Growth In Vitro and In Vivo and Enhances the Anti-MM Effects of Melphalan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 843-843
Author(s):  
Eric SancheZ ◽  
Richard A Campbell ◽  
Jeffrey A Steinberg ◽  
Mingjie Li ◽  
Haiming Chen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Tumor Volume ◽  
Single Agent ◽  
Human Tumor ◽  
The Novel

Abstract Proteasome inhibitors (PI) have been shown to be effective agents for the treatment of multiple myeloma (MM) and enhance the anti-tumor effects of a variety of chemotherapeutic drugs including melphalan and doxorubicin as well as arsenic trioxide (ATO). The novel proteasome inhibitor CEP-18770 has recently been shown to induce cytotoxic effects across a broad panel of human tumor cell lines including MM in vitro. However, little data exists on the in vivo anti-MM effects of this PI either alone or in combination with other active anti-MM drugs. First, we examined the anti-proliferative effects of treating MM cell lines in vitro with CEP-18770 alone and in combination with melphalan, arsenic trioxide (ATO) and doxorubicin. MM cell lines were cultured without fetal bovine serum and incubated in the presence of CEP-18770 alone and in combination with these agents for 48 hours. Cell growth was then measured using an MTS assay. First, RPMI8226 and U266 cells were tested in vitro using a constant concentration of melphalan or doxorubicin in combination with varying concentrations of CEP-18770 or varying concentrations of the chemotherapeutic agent with constant CEP-18770. Although single agent treatment showed marked anti-proliferative effects, combination indexes as calculated by the Chou-Talalay method showed synergistic anti- MM effects of CEP-18770 with either melphalan or doxorubicin in these MM cell lines. In addition, similar experiments were carried out evaluating the combination of ATO plus CEP-18770 in RPMI8226 cells and also showed synergism with this combination. Next, a series of in vivo studies were conducted using our SCID-hu models of MM including LAGλ-1, LAGκ-1A and LAGκ-1B. Mice receiving CEP-18770 at 0.1, 0.3, 1, and 3 mg/kg were injected twice weekly via intravenous injection throughout the study. CEP-18770 dosed at 10 mg/kg was administered via oral gavage twice weekly and mice dosed with melphalan received injections once weekly via intraperitoneal injection. Mice bearing intramuscularly implanted LAGλ-1 were treated with CEP-18770 or vehicle alone. Mice treated with the PI inhibited tumor growth as determined by human immunoglobulin (hIg) G levels and measurement of tumor volume (P = 0.0008) compared to mice receiving vehicle. A significant inhibition of both human paraprotein secretion and reduction of tumor growth was also observed in LAGk-1A-bearing mice treated with CEP-18770 at 1, 3 and 10 mg/kg (hIgG: P = 0.0001, P = 0.0002 and P = 0.0001, respectively; tumor volume: P = 0.0001, P = 0.0001 and P = 0.0001, respectively) and LAGk-1B-bearing mice treated with CEP-18770 at 3 and 10 mg/kg (hIgG: P = 0.0008 and P = 0.0034, respectively; tumor volume: P = 0.0008 and P = 0.0028, respectively) compared to mice receiving vehicle. Finally, the combination of CEP-18770 (1 mg/kg) plus melphalan (3 mg/kg) was tested in LAGk-1B-bearing mice. Mice treated with the combination showed markedly smaller tumors compared to treatment with vehicle (P = 0.0008) or melphalan alone (P = 0.0204). Mice treated with the PI alone or in combination with melphalan did not show any observed toxicity. Thus, these studies provide promising preclinical data to suggest the potent anti-MM effects of CEP-18770 both in vitro and in vivo and also suggest that this new PI may enhance the anti-MM effects of several active anti-MM agents including melphalan, doxorubicin and ATO.

Effects of Oprozomib in Combination with Pomalidomide and/or Dexamethasone on Human Multiple Myeloma Tumors Growing in SCID Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5349-5349 ◽  
Author(s):  
Eric Sanchez ◽  
Mingjie Li ◽  
Abigail Gillespie ◽  
Puja Mehta ◽  
Suzie Vardanyan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Size ◽  
Research Funding ◽  
Single Agent ◽  
Xenograft Model ◽  
Tumor Burden ◽  
Scid Mice ◽  
Human Multiple Myeloma ◽  
Minimal Reduction

Abstract Introduction: Oprozomib (OPZ) is an irreversible, orally administered proteasome inhibitor (PI).It decreases tumor burden and prevents tumor-related bone loss in preclinical multiple myeloma (MM) studies. In recently published clinical trials, the combination of the PI carfilzomib with the immunomodulatory agent (IMiD) lenalidomide and dexamethasone (Dex) has shown high response rates with durable responses for previously treated and untreated MM patients. Carfilzomib with the IMiD pomalidomide (Pom) and Dex for the treatment of RRMM patients shows promising results (Shah et al, 2013). We evaluated OPZ in combination with Pom and Dex using two of our human MM xenograft models in severe combined immunodeficient (SCID) mice. Methods: Each SCID mouse (n=10/group) was surgically implanted with a 20 - 40 mm3 MM tumor piece into the hind limb. Seven days post-implantation mice were randomized into treatment groups based on human immunoglobulin (Ig) G levels. OPZ stock solution (4 mg/ml) was diluted to 40 mg/kg using 1% carboxymethylcellulose (CMC) and administered twice weekly on two consecutive days via oral gavage.Dex stock solution (10 mg/ml) was diluted to 1 mg/kg using NaCl and administered daily via intraperitoneal injection.Pom stock solution (1 mg/ml) was diluted to 10 mg/kg using 1% CMC and administered daily via oral gavage. Tumor size was measured using calipers and IgG levels by ELISA. Results: Using our human MM model LAGk-1A, treatment with single agent OPZ or Pom produced a minimal reduction in tumor volume when compared with vehicle-treated mice, whereas Dex alone or OPZ + Pom produced more anti-MM effects, and no differences were observed between these two groups. Mice treated with OPZ + Dex or Pom + Dex also showed greater anti-MM activity than OPZ + Pom or Dex alone but the differences were not significant. All three agents together resulted in much smaller tumors when compared to OPZ + Pom on days 35, 42, 49 and 56 (P = 0.0006, P = 0.0001, P = 0.0002 and P < 0.0001, respectively). The same triplicate resulted in a smaller tumors when compared to OPZ + Dex on days 35, 42, 49, 56, and 63 (P = 0.0112, P = 0.0030, P = 0.0060, P = 0.0035 and P = 0.0021, respectively). Although Pom + Dex had some anti-MM effects when compared to the three single agents and one of the doublets (OPZ + Pom), mice receiving the triplicate demonstrated markedly smaller tumors when compared with Pom + Dex on days 35, 42, 49, 56, 63, 70, and 77 (P = 0.0250, P = 0.0018, P < 0.0001, P = 0.0014, P = 0.0018, P = 0.0017 and P = 0.0014, respectively). Mice receiving Pom + Dex had to be euthanized on day 77, whereas mice receiving all three drugs had very small tumors at study termination. We obtained similar results in a second MM xenograft model that produces IgG (LAGλ-1). Although day 21 post-tumor implantation mice receiving Pom alone had lower IgG levels compared with vehicle-treated mice (P = 0.0053), mice receiving OPZ + Pom had smaller tumors when compared to Pom alone (P = 0.0387), OPZ alone (P = 0.0004), or vehicle-treated mice (P = 0.0001). Although mice receiving Pom alone had a reduction in tumor size when compared with vehicle-treated mice (P = 0.0021), mice receiving OPZ + Pom had smaller tumors when compared with Pom alone (P = 0.0081), OPZ alone (P = 0.0007), or vehicle-treated mice (P < 0.0001). Mice receiving the triplicate showed smaller tumors on day 28 compared with mice treated with either the doublets of Pom + Dex (P = 0.0120) or OPZ + Pom (P = 0.0043). Conclusions: These in vivo human MM xenograft studies show that the combination of OPZ + Pom + Dex shows greater anti-MM activity than doublets (Pom + Dex, OPZ + Dex or OPZ + Pom) or single agents, and provides further support for this three drug combination to treat MM. Disclosures Tang: Onyx: Research Funding. [email protected]:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Novel Bruton's Tyrosine Kinase Inhibitor Bgb-3111 Demonstrates Potent Activity in Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5374-5374 ◽  
Author(s):  
Carrie J Li ◽  
Yang Liu ◽  
Taylor Bell ◽  
Jack Wang ◽  
Hui Guo ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Viability ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Mantle Cell ◽  
Btk Inhibitor ◽  
Dose Dependent

Abstract Background: Aberrant B-cell receptor signaling is an important contributor to lymphomagenesis in mantle cell lymphoma (MCL). Bruton's Tyrosine Kinase (BTK), a component of the BCR signaling axis, has been validated as a clinically relevant target, and BTK inhibitor ibrutinib received FDA approval for treatment of MCL in 2013. Growing concerns that single agent ibrutinib exerts off-target effects that interfere with other treatments such as rituximab-induced antibody-dependent cell cytotoxicity limit its utility in combination treatments. In this study, we assessed the in vitro and in vivo effects of BGB-3111in MCL models. Methods: We performed cell viability assays with BGB-3111 treated MCL cell lines to determine inhibition of cellular proliferation. The same assays were conducted on primary human MCL cells and patient-derived xenograft (PDX) tumor samples. Dose-dependent inhibition of BTK auto-phosphorylation and inhibition of downstream targets such as PLC-γ were determined by phospho-protein immunoblotting and immunoprecipitation. A reverse-phase protein assay (RPPA) was conducted on BGB-3111-treated Mino cells to evaluate changes in MCL oncogenic signaling. Induction of apoptosis in MCL cells treated with increasing doses of BGB-3111 was quantified using flow cytometry. For in vivo experiments, an ibrutinib-sensitive MCL PDX mouse model was treated with 50 mg/kg/day BGB-3111 and monitored for mean tumor burden and survival. Results: BGB-3111 potently inhibited cell viability in a panel of MCL cell lines, with an activity range of 1-10 uM, and induced apoptosis in a dose-dependent manner in several MCL cell lines.BGB-3111 treatment of MCL cells demonstrated a dose-dependent decrease in p-BTK (Y223) and inhibition of downstream effectors without impacting total protein levels, while RPPA revealed upregulation of the PI3K-Akt signaling axes. In addition, BGB-3111 treatment did not impact phosphorylation of off-target kinases affected by ibrutinib treatment. In vivo, BGB-3111 suppressed tumor growth and prolonged tumor survival in BGB-3111 treated mice. Conclusion: The second generation BTK inhibitor BGB-3111 demonstrates selectivity for BTK in vitro and BTK inhibition in vivo. BGB-3111-treated PDX mouse models examining survival, tumor growth, and other factors point to BGB-3111 as an effective single agent BGB-3111 is being investigated in Phase I clinical trials. Disclosures Wang: Beigene: Employment. Wang:Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Acerta: Consultancy, Research Funding; Kite Pharma: Research Funding; BeiGene: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding.

Anti-Myeloma Effects of the Novel Anthracycline Derivative INNO-206

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5107-5107
Author(s):  
Eric Sanchez ◽  
Cydney M Nichols ◽  
Alison C Lam ◽  
Mingjie Li ◽  
Cathy Wang ◽  
...  
Keyword(s):  
Research Funding ◽  
Tumor Volume ◽  
Statistical Significance ◽  
Volume Growth ◽  
Pegylated Liposomal Doxorubicin ◽  
Scid Mice ◽  
Weekly Dose ◽  
The Novel ◽  
Higher Doses

Abstract Abstract 5107 Introduction: Doxorubicin and pegylated liposomal doxorubicin have recently shown efficacy for the treatment of multiple myeloma (MM). However, the efficacy of these drugs as single agents and in combination therapies is limited by their myelosuppressive, cardiac and dermatological side effects. INNO-206 (CytRx Corporation, Los Angeles, CA) is an albumin-binding prodrug of doxorubicin that is released from albumin under acidic conditions. The bone marrow of MM patients is often acidic due to the increased activity of osteoclasts that allow free doxorubicin to be released from INNO-206. Following intracellular uptake, the drug is released in the acidic endosomal or lysosomal compartments. Thus, this drug offers the possibility of achieving higher levels of active doxorubicin near and within tumor cells than with conventional doxorubicin. Our laboratory has previously evaluated this compound in vivo using one of our SCID-hu MM models of MM and determined the anti-MM effects and toxicity of INNO-206 (10.8 mg/kg) alone when compared to conventional doxorubicin (4 and 8 mg/kg), both administered weekly via intravenous (i.v.) injection, using our severe combined immunodeficient (SCID) murine model of human MM, LAGk-1A. INNO-206 was able to be administered safely at much higher doses than conventional doxorubicin, and this novel anthracycline showed excellent anti-MM effects. However, the optimal dose and schedule of INNO-206 was not determined. Thus we set out to determine at what dose and schedule INNO-206 would provide the highest anti-MM activity with the lowest amount of drug using two of our MM xenograft models (LAGk-1A, LAGk-2). Methods: Each SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and mice randomized into treatment groups. INNO-206 stock solution was prepared using 50% ethanol and 50% water, and diluted to the appropriate dose in water. It was administered to LAGk-1A-bearing SCID mice at 5.4 mg/kg once weekly and 1.8 mg/kg thrice weekly via i.v. injection. Mice were bled for hIgG levels and the intramuscular tumors were measured using standard calipers on a weekly basis. Data was analyzed as the mean ± SEM. These studies were conducted according to protocols approved by the Institutional Animal Care and Use Committee. Results: SCID mice bearing LAGk-1A treated once weekly with INNO-206 at 5.4 mg/kg showed markedly smaller tumor volumes on day 56 compared to vehicle-treated mice (P = 0.0413). At day 56 post tumor implantation, 9/10 control mice were alive versus 8/10 mice alive in the 5.4 mg/kg INNO-206 group. In contrast, we also evaluated INNO-206 at 1.8 mg/kg administered thrice weekly (dose equivalent to 5.4 mg/kg INNO-206 once weekly), on consecutive days, which resulted in moderate tumor volume growth inhibition but not statistical significance. Additionally, we evaluated various doses and schedules of INNO-206 (0.9 mg/kg-10.8 mg/kg) in the LAGk-2 tumor and significant inhibition of tumor volume growth was observed two weeks into treatment with INNO-206 alone and in combination with bortezomib when compared to vehicle treated mice. Conclusions: We have shown that the novel anthracycline INNO-206 shows marked anti-MM effects in vivo using our SCID-hu MM models LAGk-1A and LAGk-2. The results from these studies suggest that this doxorubicin conjugate may provide MM patients with a new anthracycline that may be able to be administered at higher doses safely resulting in superior efficacy compared to the currently available anthracyclines to treat this B-cell malignancy. Disclosures: Berenson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding.

Anti-Myeloma Effects of Carfilzomib with Cyclophosphamide (CY) or Bendamustine (Ben).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2952-2952
Author(s):  
Eric Sanchez ◽  
Mingjie Li ◽  
Cathy Wang ◽  
Haiming Chen ◽  
James R. Berenson
Keyword(s):  
Clinical Trials ◽  
Tumor Growth ◽  
Treatment Regimen ◽  
Combination Treatment ◽  
Tumor Size ◽  
Tumor Volume ◽  
Single Agent ◽  
Lower Percentage ◽  
Vehicle Group ◽  
Combination Regimen

Abstract Abstract 2952 Introduction: Carfilzomib (Onyx Pharmaceuticals, South San Francisco, CA, USA) is an irreversible proteasome inhibitor (PI) that has shown preclinical and clinical efficacy against multiple myeloma (MM). It has shown clinical benefit as a single agent and with steroids in early clinical trials, even among patients resistant to prior bortezomib treatment. We determined the anti-MM effects of carfilzomib in combination with cyclophosphamide (CY) or bendamustine (Ben) in vivo using our xenograft model of human MM, LAGk-1A. Methods: Each SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the hind limb. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and mice randomized into groups. Carfilzomib stock solution (2 mg/ml) was diluted to 3 mg/kg using 10% capsitol and administered twice weekly via intravenous (i.v.) injection. Cyclophosphamide (Baxter, Deerfield, IL, USA) stock solution (20 mg/ml) was diluted in sodium chloride and administered via oral gavage once weekly at 10 mg/kg. Bendamustine (Teva Pharmaceuticals, North Wales, PA, USA) stock solution (5 mg/ml) was diluted to 5 mg/kg in sterile water and administered via intraperitoneal (i.p.) once weekly. Mice (n = 8) were bled to determine hIgG levels and the tumors were measured using standard calipers. Data was analyzed as the mean ± SEM. Results: LAGk-1A-bearing mice treated with single agent carfilzomib or CY did not show a reduction in tumor growth compared to vehicle-treated mice. In contrast, the combination of carfilzomib plus CY resulted in a statistically significant decrease in tumor size and IgG levels when compared to vehicle-treated mice on days 35, 42, 49, and 56 (tumor volume; P = 0.0007, P = 0.0003, P = 0.0008 and P = 0.0001: IgG levels; P = 0.0023, P = 0.0327, P = 0.0219 and P = 0.0190, respectively). Toxicity was minimal as seven of eight mice survived this combination regimen. Furthermore, tumor growth delay (TGD) to a volume of 1,125 mm3 was delayed by 53.6% (22 days, day 41 for control compared to day 63 for the carfilzomib + CY group) among animals receiving this combination treatment regimen when compared to vehicle-treated animals. In contrast, shorter TGDs were obtained when mice were dosed with single agents. When mice were dosed with carfilzomib alone, a TGD of 12.1% (5 days, day 41 for control compared to day 46 for the carfilzomib group) was obtained. When mice were dosed with CY alone, a TGD of 26.8% (11 days, day 41 for control compared to day 52 for the CY group) was obtained. Percentage inhibition of tumor growth (T/C) is represented as the median tumor volume of the test drug group over the median tumor volume of the vehicle group. A T/C ratio of ≤42% is indicative of drug efficacy. At day 56 post tumor implantation, mice receiving single agent treatment with carfilzomib or CY had T/C's of 88% and 67%, respectively. In contrast, at the same time point, mice receiving the cafilzomib plus CY regimen resulted in a lower percentage T/C of 29%. We also evaluated the combination of carfilzomib plus Ben in LAGk-1A-bearing mice. Animals treated with single agents did not result in a reduction in tumor volume compared to vehicle-treated mice. In contrast, the combination of carflzomib and Ben resulted in a decrease in tumor size compared to vehicle-treated mice on days 35, 42, 49, and 56 (P = 0.0184, P < 0.0001, P = 0.0035, and P = 0.0026, respectively). Additionally, this combination resulted in a reduction in IgG levels compared to vehicle-treated mice on days 42, 49 and 56 (P = 0.0426, P = 0.0257 and P = 0.0204, respectively). Furthermore, six of eight mice survived this treatment regimen. Compared to vehicle-treated mice, animals treated with the combination treatment showed a TGD to 1,250 mm3 of 38% (16 days, day 42 for control compared to day 58 for the carfilzomib + Ben). When compared to vehicle-treated mice, carfilzomib-treated animals showed a TGD of only 14.3% (6 days, day 42 for control compared to day 48 for the carfilzomib), and there was no TGD for mice treated with Ben alone. Conclusions: We have shown that the combination of carfilzomib plus CY or Ben shows marked anti-MM effects using our xenograft MM model LAGk-1A. The results from these preclinical studies provide the basis for clinical trials evaluating the combination of carfilzomib with CY or Ben for patients with MM. Disclosures: Berenson: Onyx: Consultancy, Honoraria, Speakers Bureau.

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