scholarly journals Contribution of Amino Acid Metabolism to Hematologic Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-10-SCI-10
Author(s):  
Marina Y. Konopleva ◽  
Philip L Lorenzi ◽  
Sanaz Ghotbaldini ◽  
Yoko Tabe ◽  
Tianyu Cai ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tyrosine Kinase ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Therapeutic Strategy ◽  
Immune Cell ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Glutaminase Activity

Abstract Tumor cells rewire metabolic pathways to meet the high metabolic demands of proliferation, frequently developing auxotrophy to specific amino acid(s) (AAs) required to satisfy protein biosynthesis. Thus specific metabolic inhibitors or AA-depleting enzymes have been developed and tested as cancer therapeutics. For example, depletion of asparagine by bacterial L-asparaginase (ASNase) has proven efficacious against hematologic malignancies, especially leukemia and lymphoma, by starving tumors lacking asparagine synthetase (ASNS). We and others have reported that the glutaminase (GLS) activity of ASNase is required for anticancer activity against ASNS-positive leukemia cell types in vitro.1 In vivo, we have found that durable response to ASNase in pre-clinical models of leukemia also requires glutaminase activity, even against ASNS-negative leukemia models; a glutaminase-deficient mutant of ASNase yielded subsequent leukemia recurrence. We speculate that the underlying anti-leukemia mechanism mediated by ASNase glutaminase activity involves a deeper depletion of asparagine within the tumor microenvironment, since ASNS in nearby cells (adipocytes, mesenchymal stromal cells, etc.) can use glutamine as a precursor for asparagine synthesis. Nevertheless, since L-glutamine depletion is thought to cause the significant side effects of ASNase, enzyme variants with reduced glutaminase coactivity are being developed and tested. Another viable therapeutic strategy involving glutamine starvation via GLS inhibitor has shown significant pre-clinical activity in acute myeloid leukemia (AML) and multiple myeloma (MM) models; this approach is synergistic with hypomethylating agents and BCL2 inhibitors in AML, and with proteasome inhibitors in MM. Recent findings highlight the switch to glutamine metabolism as a metabolic dependency of tyrosine kinase-driven AML, and targeting GLS in conjunction with tyrosine kinase inhibition has been proposed.2 Targeting arginine metabolism has been shown to be another viable therapeutic strategy. Arginine (ARG) depletion using pegylated arginine deaminase (ADI-PEG 20) or pegylated arginase (PEG-ARGase), the 2 critical enzymes of the ARG metabolism/urea cycle, reduced leukemia tumor burden in AML models characterized by low arginosuccinate synthetase (ASS) and high uptake of ARG. However, recently reported Phase I/II clinical trials of recombinant PEG-arginase and of ADI-PEG 20 showed minimal efficacy in relapsed/refractory AML and in solid tumors despite efficient depletion of arginine and low ASS1 expression in tumors, indicating that depletion of arginine alone is insufficient for clinical activity. As a final example of AA metabolic pathways targeted in the treatment of hematologic malignancies, exogenous L-cysteine is required for the synthesis of glutathione for antioxidant cellular defense. In pre-clinical studies, multiple malignancy subtypes were sensitive to cysteine and cystine degradation by an engineered human cyst(e)inase enzyme, including AML, acute lymphocytic leukemia, poor-risk chronic lymphocytic leukemia (CLL), and MM.3 In all therapeutic strategies targeting AA metabolism, the tumor microenvironment may contribute to resistance. For example, bone marrow stromal cells efficiently import cystine, convert it to cysteine, and transport it to CLL cells, facilitating leukemia chemoresistance. Mesenchymal stromal cells and bone marrow adipocytes secrete asparagine and glutamine, respectively, and protect leukemia cells from ASNase cytotoxicity. Recent insights into the immune tumor microenvironment highlight interplay between tumor, AAs, and immune cell functions. Some AAs, such as arginine and glutamine, are essential nutrients for immune cell proliferation and metabolism; excessive tumor consumption of glutamine, or secretion of arginase by myeloid-derived suppressor cells or AML blasts, may deprive immune cells, impair T cell proliferation, and induce immunosuppressive phenotypes. GLS inhibitors that block glutamine consumption and arginase inhibitors that increase plasma arginine, increase availability of their respective target nutrients for immune cells and are, therefore, being explored in ongoing clinical trials as monotherapies and in combination with anti-PD1 blockade. Chan WK, Lorenzi PL, Anishkin A, et al. The glutaminase activity of L-asparaginase is not required for anticancer activity against ASNS-negative cells. Blood. 2014;123:3596-3606. Gallipoli P, Giotopoulos G, Tzelepis K, et al. Glutaminolysis is a metabolic dependency in FLT3(ITD) acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition. Blood. 2018;131:1639-1653. Zhang W, Trachootham D, Liu J, et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat Cell Biol. 2012;14:276-286. Disclosures Konopleva: Stemline Therapeutics: Research Funding. Lorenzi:Erytech Pharma: Consultancy; NIH: Patents & Royalties.

scholarly journals Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4353-4358 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop Kantarjian ◽  
Sara S. Strom ◽  
Mary Beth Rios ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Myeloproliferative Neoplasm ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Second Cancers

Abstract Success of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has given patients hope for a long disease-free-survival. A longer survival raises the question of late effects, including development of another malignancy. Records of 1445 patients with CML/myeloproliferative neoplasm or other hematologic malignancies treated with TKIs were reviewed to investigate frequency and characteristics of second malignancies (other than acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndrome). The number of second cancers was compared with the number expected from the Surveillance, Epidemiology, and End Results database. After a median follow-up of 107 months (range, 13-362 months) after CML/myeloproliferative neoplasm diagnosis, 66 patients (4.6%) developed 80 second cancers, including skin (31%), prostate (15%), melanoma (13%), digestive system (10%), kidney (4%), thyroid (4%), breast (3%), chronic lymphocytic leukemia (3%), hepatobiliary (3%), and other cancers (14%). Excluding nonmelanoma skin cancers, 55 second cancers were seen in 51 (3.5%) of all patients treated. The risk of second cancer was lower than expected (observed-to-expected ratio, 0.6; 95% confidence interval, 0.44-0.81). Second cancers occur in a small percentage of patients receiving therapy with TKIs for hematologic malignancies, mostly CML. No evidence at the moment suggests that exposure to TKIs increases the risk of developing second cancers.

scholarly journals Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3334-3334 ◽  
Author(s):  
Susan O'Brien ◽  
Manish Patel ◽  
Brad S. Kahl ◽  
Steven M. Horwitz ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Microenvironment ◽  
Research Funding ◽  
Dose Range ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Proliferation Index ◽  
Clinical Activity ◽  
Cytokines And Chemokines ◽  
Cell Proliferation Index

Abstract Introduction: Signaling via PI3K-δ and PI3K-γ has distinct and complimentary effects on malignant B-cells and nonmalignant immune cells important in tumor immunity, and on the tumor microenvironment involved in the support and maintenance of B-cell neoplasms, including chronic lymphocytic leukemia (CLL). Duvelisib (IPI-145), a novel targeted oral PI3K-δ,γ inhibitor, is in development for the treatment of hematologic malignancies. An ongoing Phase 1 study has demonstrated substantial clinical activity in patient (pts) with relapsed/refractory (R/R) CLL, including those with poor prognostic risk factors. Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity of duvelisib administered in pts with advanced hematologic malignancies. Pharmacodynamic (PD) studies included peripheral blood (PB) flow cytometry to evaluate whether duvelisib inhibits phosphorylation of AKT (pAKT) and proliferation (Ki67) in CLL cells and serum sampling to evaluate modulation of cytokines and chemokines important for tumor microenvironment signaling. Genomic DNA was isolated from PB at baseline for Sanger sequencing of IGHV and next-generation sequencing of TP53. Following dose escalation, expansion cohorts enrolled CLL pts at 25 and 75 mg BID (MTD). Response was based on IWCLL (2008) criteria. Results: The median age of the R/R CLL pts (n=54) was 66 y (range 42-82), 78% of whom were male. Forty-four (81.5%) pts received ≥3 prior systemic therapies. The median time from prior therapy to first dose of duvelisib was 3.5 mo (range 0-39.1). Baseline cytopenias ≥ Grade 2 were neutropenia (41%), thrombocytopenia (31%) and anemia (26%). Of the pts with baseline tests for mutations associated with poor CLL prognosis, 49% (23/47) had TP53mut and/or cytogenetic (del)17p and 89% (31/35) had an unmutated IGHV. Duvelisib dosed at 25 mg BID provided an optimal biologic effect based on maximum pAKT inhibition in CLL cells (<24 hrs after a single dose) and reductions in serum cytokines and chemokines (by Cycle 1 Day 8) known to contribute to CLL growth and survival. In addition, median CLL cell proliferation index (Ki67) was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state). These PD effects were similar at higher doses (75 mg BID). On-target lymphocytosis had a rapid onset (maximum mean absolute lymphocyte count [ALC] by Cycle 1 Day 8) across the dose range evaluated (8 to 75 mg BID), returning to baseline (mean ALC) by Cycle 4 Day 1 (12 wks on treatment). In pts with baseline CT assessments, 83% (38/46) achieved >50% reduction in adenopathy by CT scan. The best overall response rate (ORR) by IWCLL criteria was 55% in 49 evaluable pts, including 1 complete response (CR) and 26 partial responses (PR). There were 21 pts with stable disease and 1 pt with progressive disease. Median time to response was 1.9 mo (range 1.7-8.3). The ORR was similar irrespective of dose (52%, ≤25 mg BID [n=29]; 60%, 75 mg BID [n=20]), or the presence of TP53mut/(del)17p (48% [n=23], including 1 CR) or unmutated IGHV (52%, n=31). Treatment emergent adverse events (AEs, all causality) were similar across the dose range and were predominantly Grade 1-2. With a median of 7.3 treatment cycles (range 1.0-30.8), the most common AEs ≥Grade 3 (≥10%, all causality) were transient cytopenias (neutropenia [31%] and thrombocytopenia [11%]), febrile neutropenia (15%), and pneumonia (11%). The most common reasons for treatment discontinuation were AEs (31%) and disease progression (24%). Conclusions: Pharmacodynamic studies in this ongoing investigation indicate duvelisib, an oral PI3K-δ,γ inhibitor, modulates pAKT in CLL cells, chemokines/cytokines involved in CLL cell survival, and CLL cell proliferation index (Ki67). Early resolution of lymphocytosis and objective lymph node responses suggest survival signals from the tumor microenvironment are affected by inhibition of PI3K-δ,γ pathways. Duvelisib continues to demonstrate clinical activity, with a best ORR of 55% (IWCLL) in a heavily pretreated R/R CLL population, including pts with poor prognostic features. The overall safety profile is generally well tolerated, consistent with underlying disease and suggests a favorable benefit-risk profile in this R/R CLL population. These results support the further development of duvelisib monotherapy, and a randomized Phase 3 study in pts with R/R CLL is ongoing. Disclosures Kahl: Infinity Pharmaceuticals: Consultancy, Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum: Consultancy, Honoraria, Research Funding. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment. Flinn:Infinity Pharmaceuticals: Consultancy.

Targeting Tyrosine Kinase Receptors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-25-SCI-25
Author(s):  
Michael Deininger
Keyword(s):  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Third Generation ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Flt3 Mutations

Abstract Protein tyrosine kinases (PTKs) regulate cell growth and other key functions. Constitutive PTK activation by somatic mutations, overexpression, or abnormal upstream signaling is characteristic of many cancers, including hematologic malignancies, providing a rationale for therapeutically targeting PTKs with small molecules. Imatinib, an ATP-competitive inhibitor of BCR-ABL1, the PTK causal to chronic myeloid leukemia (CML), established a paradigm for tyrosine kinase inhibitors (TKIs) as cancer therapeutics. Although a relatively weak inhibitor, imatinib is effective in most patients with chronic phase CML (CML-CP), while responses are transient in blastic phase (CML-BP). Point mutations in the BCR-ABL1 kinase domain have emerged as a major mechanism of drug resistance. The more potent second-generation TKIs – dasatinib, nilotinib, and bosutinib – induce deeper and faster responses and are active against many imatinib-resistant mutants, with the exception of T315I in the gatekeeper position of the catalytic site. This problem was addressed with ponatinib, a third-generation TKI covering all single BCR-ABL1 mutants, including T315I. Ponatinib has excellent clinical activity in CML-CP patients who failed other TKIs, while responses in CML-BP are short-lived. Some patients fail ponatinib due to BCR-ABL1 compound mutations, suggesting even third-generation TKIs cannot completely prevent mutational escape by the disease-initiating kinase. Another unsolved problem is that TKIs fail to efficiently target CML stem cells, leading to recurrence of active leukemia upon discontinuation. Despite these shortcomings, TKIs have completely changed the face of CML. Unfortunately, repeating this success in other hematologic malignancies has been challenging, likely reflecting differences in disease biology as much as suboptimal design of early compounds. CML-CP represents one extreme of the spectrum, where a single genetic lesion is sufficient to produce the phenotype and the hierarchy of hematopoietic differentiation is maintained. The situation is different in acute myeloid leukemia (AML) with activating FLT3 mutations. Not only these AML cases have mutations in other genes, they typically acquire FLT3 mutations late during disease evolution, implying that the disease-initiating clone will be impervious to FLT3 inhibition. Progress has been made through successive development of more potent TKIs with improved pharmacology, leading to quizartinib. It is clear, however, that FLT3 inhibitors cannot be used as single agents if there is a curative intent and the same may be true for JAK2 inhibitors in myelofibrosis. The first approved JAK2 inhibitor, ruxolitinib, dramatically improves symptoms, but has yet to demonstrate a significant impact on the malignant clone and is certainly not curative. It remains to be seen whether this reflects the fact that JAK2 activation is not the disease–initiating event, lack of inhibitor specificity towards the mutant JAK2 kinase, or other undesirable off-target effects that may be overcome with improved drugs. A completely new chapter was opened with ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of chronic lymphocytic leukemia (CLL). BTK is essential for signal transduction from the B-cell receptor (BCR). No activating mutations in BTK have been identified in lymphoma or CLL, but constitutive BCR signaling is critical to CLL cell survival in the microenvironment. Early studies show excellent clinical activity in patients with advanced CLL, although many responses are incomplete; much like the imatinib responses in late CML-CP. Ibrutinib may have a similarly profound effect upon CLL as imatinib on CML, but perhaps also similar limitations, such as the inability to eradicate residual leukemia; this of course needs to be tested in frontline studies. TKIs have had a significant albeit uneven impact upon treatment paradigms in hematologic malignancies. Future progress will involve optimizing compounds in terms of potency, selectivity, and pharmacokinetics. Allosteric inhibitors may add to the armamentarium. From the target perspective, it is likely that most activated kinase alleles have been discovered and the focus should shift to identification of disease-critical unmutated kinases. Lastly, identifying synthetically lethal inhibitor combinations will be critical to fully exploit the potential of TKI therapy. Disclosures: Deininger: BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity’s Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CELGENE: Research Funding; GENZYME: Research Funding; INCYTE: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GILEAD: Research Funding.

Patient-derived micro-organospheres recapitulate tumor microenvironment and heterogeneity for precision oncology.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3076-3076
Author(s):  
Shengli Ding ◽  
Zhaohui Wang ◽  
Marcos Negrete Obando ◽  
Grecia rivera Palomino ◽  
Tomer Rotstein ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Tumor Biology ◽  
Cell Types ◽  
Precision Oncology ◽  
Original Tumor

3076 Background: Preclinical models that can recapitulate patients’ intra-tumoral heterogeneity and microenvironment are crucial for tumor biology research and drug discovery. In particular, the ability to retain immune and other stromal cells in the microenvironment is vital for the development of immuno-oncology assays. However, current patient-derived organoid (PDO) models are largely devoid of immune components. Methods: We first developed an automated microfluidic and membrane platform that can generate tens of thousands of micro-organospheres from resected or biopsied clinical tumor specimens within an hour. We next characterized growth rate and drug response of micro-organospheres. Finally, extensive single-cell RNA-seq profiling were performed on both micro-organospheres and original tumor samples from lung, ovarian, kidney, and breast cancer patients. Results: Micro-organospheres derived from clinical tumor samples preserved all original tumor and stromal cells, including fibroblasts and all immune cell types. Single-cell analysis revealed that unsupervised clustering of tumor and non-tumor cells were identical between original tumors and the derived micro-organospheres. Quantification showed similar cell composition and percentages for all cell types and also preserved functional intra-tumoral heterogeneity.. An automated, end-to-end, high-throughput drug screening pipeline demonstrated that matched peripheral blood mononuclear cells (PBMCs) from the same patient added to micro-organospheres can be used to assess the efficacy of immunotherapy moieties. Conclusions: Micro-organospheres are a rapid and scalable platform to preserve patient tumor microenvironment and heterogeneity. This platform will be useful for precision oncology, drug discovery, and immunotherapy development. Funding sources: NIH U01 CA217514, U01 CA214300, Duke Woo Center for Big Data and Precision Health

scholarly journals Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1931-1941 ◽  
Author(s):  
A Neubauer ◽  
A Fiebeler ◽  
DK Graham ◽  
JP O'Bryan ◽  
CA Schmidt ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Hematopoietic Tissue ◽  
Blood Leukocytes

Abstract We previously reported the cloning, and characterization of a receptor tyrosine kinase, axl, from two patients with chronic myelogenous leukemia. Herein, we describe the expression pattern of axl in normal and malignant hematopoietic tissue axl message is detected in normal human bone marrow but not significantly in normal blood leukocytes. Cell separation experiments showed that axl is expressed in hematopoietic CD34+ progenitor and marrow stromal cells, at low levels in peripheral monocytes, but not in lymphocytes or granulocytes. Consistent with the normal pattern of axl expression, axl RNA was found predominantly in diseases of the myeloid lineage: 39 of 66 (59%) patients with myeloproliferative disorders (acute myeloid leukemia, chronic myeloid leukemia (CML) in chronic phase, CML in myeloid blast crisis, and myelodysplasia) showed significant axl transcription, as compared with 1 of 45 (2%) lymphoid leukemias (chronic lymphocytic leukemia, acute lymphocytic leukemia, and CML in lymphoid blast crisis). Treatment of K562 cells with the phorbol ester, 12-O- tetradecanoylphorbol-13-acetate (TPA), administration of interferon alpha (IFN alpha) to normal monocytes, and treatment of U937 cells with TPA and IFN tau significantly induced axl expression, supporting a role for this kinase in the intracellular signaling of myeloid cells through a variety of biochemical pathways. These results suggest that the axl kinase may be operative in normal and malignant myeloid biology.

CAL-101, a Potent Selective Inhibitor of the p110δ Isoform of Phosphatidylinositol 3-kinase, Attenuates Pathway Signaling, Induces Apoptosis, and Overcomes Signals From the Microenvironment In Cellular Models of Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3926-3926 ◽  
Author(s):  
Sarah A Meadows ◽  
Adam Kashishian ◽  
Dave Johnson ◽  
Volker Diehl ◽  
Brian Lannutti
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Stromal Cells ◽  
Specific Inhibitor ◽  
Lymphocytic Leukemia ◽  
Class I ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Cellular Models ◽  
Dose Dependent

Abstract Abstract 3926 Phosphatidylinositide 3-kinases (PI3Ks) are a family of lipid kinases that are involved in signaling events which control a diverse number of cellular processes. The class I kinases contain 4 isoforms designated p110α, β, δ, γ, and are activated by cell surface receptors. Aberrant regulation of the PI3K signaling pathway is frequently observed in human malignancies including those of hematological origin. CAL-101 is an oral p110δ-specific inhibitor which has shown preclinical and clinical activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This compound is a potent p110δ inhibitor (EC50 of 65 nM in a whole-blood assay) with >200-fold selectivity over the other class I PI3K isoforms and no activity against Class II and III PI3K family members or other PI3K-related proteins, including mTOR and DNA-PK. Prior in vitro NHL studies revealed that CAL-101 induces caspase-dependent apoptosis, and inhibits CD40L-, BAFF-, CXCL12- and CXCL13-derived survival signals in cellular models (Lannutti BJ, et al., Blood 2010). To investigate the potential role of p110δ in Hodgkin lymphoma (HL) we screened a number of HL cell lines for p110δ isoform expression and constitutive PI3K pathway activation. We report high levels of p110δ protein and activated Akt in 5 of 5 HL cell lines evaluated (L428, L540, L591, L1236, KM-H2). Inhibition of p110δ with CAL-101 treatment of cell lines resulted in a reduction of Akt phosphorylation and a decrease in cellular viability. Because previous studies have established the importance of signals from the microenvironment for the survival and proliferation of malignant cells as well as for their resistance to standard therapies, we investigated the effect of p110δ inhibition by CAL-101 in HL cell line-stroma cocultures. In this setting, CAL-101 overcame tumor cell growth induced by coculture of HL cells with bone marrow stromal cells. In addition, CAL-101 induced dose-dependent apoptosis of HL cells at 48 hours. Furthermore, stromal cell coculture resulted in increased CCL5, CCL17, and CCL22 levels; productions of these chemokines by HL cells cultured in the presence of stromal cells were reduced by CAL-101 in a dose-dependent manner. These results indicate that specific inhibition of p110δ may disrupt signals between HL cells and their microenvironment, thereby providing the preclinical rationale for clinical evaluation of CAL-101 as a novel therapeutic approach in patients with Hodgkin lymphoma. Disclosures: Meadows: Calistoga Pharmaceuticals: Employment. Kashishian:Calistoga Pharmaceuticals: Employment. Johnson:Calistoga Pharmaceuticals: Employment. Lannutti:Calistoga Pharmaceutical Inc.: Employment.

TGR-1202, a Novel Once Daily PI3Kδ Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1984-1984 ◽  
Author(s):  
Howard A. Burris ◽  
Manish R. Patel ◽  
Danielle M. Brander ◽  
Owen A. O'Connor ◽  
Changchun Deng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Employment Equity ◽  
Previous Formulation ◽  
Equity Ownership

Abstract Background: TGR-1202 is a novel oral, next generation PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors. Preliminary data from an ongoing Ph I study of TGR-1202 demonstrated clinical activity in patients with advanced hematologic malignancies (ASCO 2014). Herein we present updated results from this Phase I, first in human study of TGR-1202 in patients with relapsed and/or refractory CLL and B-cell lymphoma. Methods: TGR-1202 is administered orally once daily following a 3+3 dose escalation design. Previously treated patients with an ECOG PS ≤ 2 and confirmed diagnosis of B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other lymphoproliferative disorders are eligible. Endpoints include safety, PK/PD, and efficacy. Results: 49 patients have been enrolled to date of various lymphoma subtypes including CLL, follicular lymphoma (FL), Hodgkin’s lymphoma (HL), DLBCL, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Demographics: 76% male, ECOG 0/1/2: 17/31/1, median age of 59 yrs (range: 22-85), median prior treatment regimens: 3 (range: 1-14), and 43% were refractory to prior treatment. 35 patients have been treated at doses ≥ 800 mg of a previous formulation where a threshold effect in activity was observed, and 6 have been treated with an improved micronized formulation (≥ 200 mg). TGR-1202 was well tolerated and no MTD has been reached to date. The only Gr≥3 AE occurring in >5% of patients was neutropenia (8%). AE’s of all grades occurring in >20% of patients were limited to diarrhea (24%), cough (22%), fatigue (20%), and nausea (20%). Notably, in comparison to other PI3Kδ inhibitors, no hepatotoxicity and no cases of colitis have been observed to date. Rates of infection and pneumonia have also been low (12% and 6%, respectively), and no cases of febrile neutropenia have been reported. Of the 41 patients treated at ≥ 800 mg of the previous formulation or with the micronized formulation, 32 are evaluable for efficacy (6 too early to evaluate, 2 non-compliant, 1 did not meet I/E criteria). Responses have been limited in patients with aggressive lymphoma and HL. Of the 9 evaluable CLL patients, 8 (89%) achieved a nodal PR (median nodal reduction of 71%), of which 5 achieved a PR per Hallek 2008 criteria with the remaining 4 having persistent lymphocytosis. The 1 CLL patient with SD had a >40% nodal reduction and remains on study. Of the 7 evaluable FL patients, all have shown clinical benefit with a reduction in tumor burden with 2 having achieved a PR, and the remaining 5 patients in SD. Additionally 2 MZL patients each achieved SD with >25% nodal reductions and remain on study. Notably, no patient with CLL or indolent lymphoma (FL & MZL) treated at ≥800 mg has progressed to date (median time on study of 20 weeks, range 6 – 73+), and no patient who achieved >50% reduction in tumor burden (including patients with CLL, FL, and HL) has progressed, with median time on study of 34 weeks (range 7 – 68+). Pharmacodynamic analysis in CLL patients indicates rapid suppression of pAKT at doses of 400 mg QD of the previous formulation. Conclusions: TGR-1202 is well tolerated in patients with relapsed and/or refractory hematologic malignancies with no reported hepatotoxicity or events of colitis and promising clinical activity. Enrollment continues in expansion cohorts and with the micronized formulation. Disclosures Brander: Celgene: Mentor received research funding Other. O'Connor:Celgene: Consultancy; Millennium Pharmaceuticals: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Flinn:Infinity Pharmaceuticals: Consultancy.

A Phase I Trial of TGR-1202, a Next Generation Once Daily PI3K-Delta Inhibitor in Combination with Obinutuzumab Plus Chlorambucil, in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2942-2942 ◽  
Author(s):  
Daruka Mahadevan ◽  
Emily K. Pauli ◽  
Kathy Cutter ◽  
Lee Ann Dietz ◽  
Peter Sportelli ◽  
...  
Keyword(s):  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Once Daily ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Btk Inhibitor ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Ecog Ps

Abstract Introduction: TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor that displays promising clinical activity in patients with relapsed and refractory hematologic malignancies, with a differentiated safety and tolerability profile compared to other PI3Kδ inhibitors (Burris, ASCO 2015). Obinutuzumab is a glycoengineered Type II anti-CD20 monoclonal antibody approved for patients with chronic lymphocytic leukemia (CLL) in combination with chlorambucil. TGR-1202 has previously been combined with a similarly glycoengineered Type I anti-CD20 mAb, ublituximab, demonstrating clinical activity in patients with heavily pre-treated hematologic malignancies (Lunning, ASCO 2015). The purpose of this study is to explore the safety and efficacy of TGR-1202 + obinutuzumab + chlorambucil in patients with CLL, evaluating a novel treatment regimen of a glycoengineered anti-CD20 with a PI3Kδ inhibitor. Methods: Eligible patients have a diagnosis of CLL/SLL with an ECOG PS ≤ 2. TGR-1202 is escalated in a 3 + 3 design. Cohort 1 was intiated at 800 mg of an initial formulation, with an improved micronized formulation introduced in Cohort 2 at 400 mg and increased in subsequent cohorts. Obinutuzumab is administered as a fixed IV infusion at 1000 mg on days 1, 8 and 15 of cycle 1, followed by day 1 of cycles 2 - 6. Chlorambucil is administered at 0.5 mg/kg on days 1 and 15 of cycle 1 and optional for cycles 2 - 6. After cycle 6, patients remain on TGR-1202 monotherapy until disease progression. Safety is the primary endpoint and is evaluated by CTCAE v. 4.0. Efficacy (ORR and duration of response) is a secondary endpoint, with responses evaluated according to IWCLL (Hallek, et. al. 2008). Results: As of August 2015, 18 patients (15 naïve/3 rel/ref) have been enrolled: Median age is 66 years (range 51-85y); 12 female/6 male, median ECOG PS = 1. FISH from the 3 relapsed patients are del13q/del17p, del11q/del17p and del11q/+12/del13q and 4 treatment naïve patients with 11q del only. All patients are evaluable for safety: AE's have been manageable, with neutropenia (61% Gr3/4), thrombocytopenia (33% Gr3/4) and increases in ALT/AST (28% Gr3/4) being the most frequent Gr3/4 events reported. Chlorambucil was discontinued in 4 patients in cycle 2 due to adverse events. No patient discontinued TGR-1202 due to ALT/AST elevations or neutropenia. 17 patients are evaluable for efficacy of which 14 were treatment naïve and 3 were previously treated, notably all 3 of which had previously progressed on a BTK inhibitor. To date, 93% (13/14) of the treatment naïve patients have achieved an objective response, including 4/14 (28%) complete responses, while 2/3 previously treated patients have achieved a response. The remaining 2 patients not in response have stable disease with 48% and 42% nodal reductions, respectively, with both remaining on study. Notably 6 of the 14 treatment naïve patients (43%) are MRD negative by peripheral blood. Conclusions: The combination of TGR-1202 + obinutuzumab + chlorambucil is well tolerated, with clinical activity observed in all patients, including patients with del17p, previously progressing on a BTK inhibitor. 7/14 (50%) of treatment naïve patients, including those with del11q, achieved either a CR or MRD negativity. Neutropenia, the highest reported AE, was manageable. Notably the ALT/AST increases observed with this combination have not been seen when TGR-1202 is administered as a single agent or in combination with another glycoengineered anti-CD20 mAb, ublituximab (<5% ALT/AST increase; N=137; O'Connor, ICML 2015). Disclosures Mahadevan: Pharmacyclics: Speakers Bureau; Alexion: Speakers Bureau. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Cutter:Clearview Cancer Center: Employment. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Schreeder:TG Therapeutics, Inc: Research Funding.

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