Short-Term Exposure to Arginine Butyrate, in Combination with Ganciclovir, Is as Effective as Continuous Exposure for Virus-Targeted Therapy of EBV-Positive Lymphomas.

Abstract Abstract 4754 Antiviral drugs alone have been unsuccessful in the treatment of Epstein-Barr virus (EBV)-associated malignancies because the virus maintains a latent state of replication in these tumors. In recent years, we developed a novel therapeutic approach wherein the early lytic phase of the virus is induced prior to the use of cytotoxic antiviral drugs. Butyrate derivatives induce an early lytic pattern of EBV gene expression in patient-derived EBV-positive lymphoblastoid cell lines and, together with the nucleoside analog ganciclovir (GCV), effectively reduce or eliminate tumor growth in humans. In a completed Phase 1/2 trial in which patients with relapsed or refractory EBV-associated lymphoid malignancies were treated with 3 weeks of Arginine Butyrate combined with GCV, tumor responses (CR and PR) occurred in 10 of 15 patients. Butyrate requires administration by prolonged intravenous infusion, which is challenging over long time periods. In the Phase 1/2 clinical trial, tumor responses were observed within a few days of starting therapy. We therefore investigated whether brief or discontinuous exposure to Butyrate is also capable of initiating early lytic-phase gene expression and thymidine kinase induction, and sensitizing EBV-positive lymphoma cells to ganciclovir-mediated cell growth arrest and apoptosis. Multiple daily 6-hr exposures of the EBV-positive Burkitt's lymphoma cell line P3HR1 to butyrate induced sustained expression of the EBV TK and lytic-phase protein BMRF. Discontinuous exposure to butyrate in combination with ganciclovir also induced a similar level of tumor cell death as did continuous treatment, as measured by serial enumeration of viable cells, MTT cell proliferation assays, and measurement of cellular DNA content. Based on these observations, we have initiated a new clinical trial utilizing a 5-day infusion of Arginine Butyrate and 21 days of GCV/valganciclovir for treatment of patients with EBV-positive lymphoid malignancies. The first patient enrolled, with Rituximab-refractory EBV-positive PTLD following a cord stem cell transplant for Hodgkin's Disease, has been treated on this protocol. The therapy was well-tolerated and resulted in rapid resolution of fever and cough of several weeks duration, and a rapid decrease of markedly elevated LDH levels to the normal range. At the end of the first cycle, 4 of 6 target lesions resolved completely, and two additional lesions decreased in size. High EBV, CMV and HHV6 viral loads became undetectable. This response has been durable for 2 months. These findings together suggest that a shorter, more patient-accessible regimen of this virus-targeted therapeutic strategy may be efficacious, and the clinical trial is continuing. Disclosures: Faller: HemaQuest Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Off Label Use: The use of Ganciclovir, administered in combination with Arginine Butyrate as an inducer of viral TK,to induce apoptosis in EBV-lymphoma and EBV lymphoproliferative disease. Ghosh:HemaQuest Pharmaceuticals: Research Funding. Lerner:HemaQuest Pharmaceuticals: Consultancy. Berenson:HemaQuest Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Perrine:HemaQuest Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.

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A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4509.4509 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4509-4509 ◽

Cited By ~ 4

Author(s):

R. Frank Cornell ◽

Adriana C Rossi ◽

Rachid Baz ◽

Craig C Hofmeister ◽

Chaim Shustik ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Low Dose ◽

Phase 1 ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results

Blood ◽

10.1182/blood.v128.22.1826.1826 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1826-1826 ◽

Cited By ~ 3

Author(s):

Martine Bagot ◽

Pierluigi Porcu ◽

Caroline Ram-Wolff ◽

Michael Khodadoust ◽

Maxime Battistella ◽

...

Keyword(s):

Clinical Trial ◽

Dose Escalation ◽

Research Funding ◽

Ex Vivo ◽

Phase 1 ◽

Clinical Activity ◽

Autologous Tumor ◽

Employment Equity ◽

T Cell Lymphomas ◽

Equity Ownership

Abstract KIR3DL2 is expressed in all subtypes of cutaneous T-cell lymphomas (CTCL), irrespective of clinical stage, with the highest prevalence of expression in Sézary syndrome (SS) and transformed mycosis fungoides (MF), two subgroups of patients with a high unmet need for clinically impactful therapies. KIR3DL2 belongs to the killer immunoglobulin-like receptor (KIRs) family and is expressed on minor subpopulations of normal NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-KIR3DL2 monoclonal antibody (mAb). It selectively depletes KIR3DL2-expressing cells by recruiting immune effectors. Its main modes of action include antibody-dependent cell-cytotoxicity (ADCC) and -phagocytosis (ADCP). IPH4102 has shown potent efficacy in preclinical models, in particular ex vivo autologous assays using primary CTCL cells. IPH4102 is currently being investigated in a first-in-human dose-finding phase 1 study (NCT02593045) evaluating repeated administrations of single-agent IPH4102 in relapsed/refractory CTCL patients. The primary objective is to assess the safety and tolerability of increasing doses of IPH4102. Secondary objectives include PK, immunogenicity and signals of anti-tumor clinical activity. Exploratory biomarkers aim to characterize KIR3DL2-expressing and non-expressing cells in involved tissue/disease compartments and to monitor changes during IPH4102 treatment. Minimal residual disease (MRD) is measured in the skin, blood and/or lymph nodes. Assessment of ex vivo NK cell-mediated ADCC against autologous tumor cells is also performed pre-dose on SS patient samples. The study has two sequential portions, a dose-escalation followed by a cohort expansion. The dose-escalation portion has a 3+3 design with accelerated titration and aims to determine the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D). In the cohort expansion portion, two CTCL subtype-specific cohorts will be studied, each to include 10 additional patients to further explore MTD or RP2D. Eligible CTCL patients must have received at least 2 lines of anti-neoplastic systemic therapy. Centrally assessed KIR3DL2 expression on malignant cells in skin or blood is required for inclusion. Patients receive IPH4102 administrations until progression or unacceptable toxicity. Intra-patient dose-escalation is allowed, only past the first complete clinical assessment at week 5 and provided the upper next dose-level is declared safe by the safety committee. Enrollment into study IPH4102-101 started in November 2015 and is currently ongoing. At time of abstract submission, dose-levels #1 to #6 have been completed. A total of 13 patients have been treated at these 6 dose-levels and are evaluable for safety and clinical activity. These patients comprise 10 SS (including 1 with evidence of large-cell transformation), 2 MF and 1 "not-otherwise-specified" CD4+ CTCL. Median age is 71 years (range 50 - 90). For these 13 patients, only grade 1 or 2 related adverse events (AEs) have been reported with IPH4102 treatment. No patient experienced a DLT or a related AE of grade ≥3. No IPH4102-related skin rashes or infections have been observed so far. Results of immuno-phenotyping of patients' blood lymphocytes show consistency of local and central assessments. In addition, ex vivo functional assay results confirm that SS patients' NK cells are functional and able to kill autologous tumor cells through ADCC with IPH4102. Our preliminary data from the phase 1 study of a novel targeted immune therapy show excellent tolerability in advanced CTCL patients. Updated results including exploratory biomarker assessment results will be presented and discussed at the meeting. Disclosures Bagot: Millenium: Other: Investigator in a clinical trial; Kiowa Hakko Kirin: Other: Investigator in a clinical trial; Innate Pharma: Equity Ownership, Other: Investigator in a clinical trial, Patents & Royalties, Research Funding. Porcu:celgene: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Ram-Wolff:Innate Pharma: Other: Investigator in a clinical trial. Battistella:Innate Pharma: Consultancy, Research Funding. Marie-Cardine:Innate Pharma: Research Funding. Mathieu:Innate Pharma: Other: Investigator in a clinical trial. Vermeer:Innate Pharma: Other: Investigator in a clinical trial. Whittaker:Seattle Genetics: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Takeda: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding. Duvic:Kiowa Hakko Kirin: Other: investigator in a clinical trial, Research Funding; Rhizen Pharmaceuticals: Other: Investigator in a clinical trial; Innate Pharma: Consultancy, Other: Investigator in a clinical trial; Millenium: Other: Investigator in a clinical trial; Angimmune LLC: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial. Bensussan:Innate Pharma: Patents & Royalties, Research Funding. Paturel:Innate Pharma: Employment, Equity Ownership. Bonnafous:Innate Pharma: Employment, Equity Ownership. Widemann:Innate Pharma: Employment. Bonin:Innate Pharma: Employment. Sicard:Innate Pharma: Employment, Equity Ownership. Paiva:Innate Pharma: Employment. Pilz:Innate Pharma: Consultancy. Kim:Kyowa Hakko Kirin: Consultancy, Honoraria, Other, Research Funding; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Consultancy, Other: Investigator in a clinical trial; Seattle Genetics: Consultancy, Other: Investigator in a clinical trial; Merck: Other: Investigator in a clinical trial; Genentech: Other: Investigator in a clinical trial; MiRagen: Consultancy; Neumedicine: Consultancy; Soligenix: Consultancy; Eisai: Consultancy, Other: Investigator in a clinical trial; Actelion: Consultancy, Other: Investigator in a clinical trial; Celgene: Consultancy; Galderma: Consultancy; Horizon: Consultancy.

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Preliminary Results of a Phase 1 Trial Evaluating MRG-106, a Synthetic microRNA Antagonist (LNA antimiR) of microRNA-155, in Patients with CTCL

Blood ◽

10.1182/blood.v128.22.1829.1829 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1829-1829 ◽

Cited By ~ 14

Author(s):

Christiane Querfeld ◽

Theresa Pacheco ◽

Francine M. Foss ◽

Ahmad S. Halwani ◽

Pierluigi Porcu ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Mycosis Fungoides ◽

Research Funding ◽

Phase 1 ◽

Human Study ◽

Employment Equity ◽

Advisory Committees ◽

Preliminary Results ◽

Equity Ownership

Abstract Introduction and Objectives: microRNAs are small, non-coding RNAs that regulate expression of multiple genes which impact physiological processes and cellular phenotypes. miR-155-5p is a well-described onco-miR with a strong mechanistic link to cutaneous T-cell lymphoma (CTCL). A LNA-modified oligonucleotide inhibitor of miR-155-5p, MRG-106, was selected based on its ability to de-repress canonical miR-155-5p targets in multiple mycosis fungoides (MF) cell lines in vitro. In preclinical models, MRG-106 showed significant pharmacodynamic activity without requiring additional formulation. The objective of this first-in-human study is to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of MRG-106 in patients with mycosis fungoides (MF). Methodology: This Phase 1 trial employs a dose-escalation design to evaluate both intratumoral and subcutaneous administration of MRG-106 at doses of 75 mg and up to 900 mg per injection, respectively. Patients were required to be ≥ 18 years old, have a confirmed diagnosis of MF, be clinical stage I-III with plaques or tumors, be on a stable treatment regimen or without any concomitant therapy for MF, and have no other major illness. The first 6 patients were dosed with four or five 75 mg intratumoral injections of MRG-106 over 2 weeks. In addition, 4 patients received saline injections in a second lesion on the same schedule. Skin biopsies were taken from MRG-106 and saline treated lesions for molecular, bioanalytical, and histological analyses, before the first dose and after the last dose. Results: Six patients (5M/1F, median age 61 years, 5 Caucasian/ 1 African-American) were dosed intratumorally. All tolerated the administrations well with only minimal erythema at the site of injection noted in one patient. One patient was discontinued from the trial due to rapid progression of disease, which was considered not related to the study drug. There were no clinically significant adverse events or laboratory abnormalities. To date, the first cohort of 6 patients has either completed the dosing period (5 patients) or discontinued due to progressive disease (1 patient). All patients showed a reduction in the baseline Composite Assessment of Index Lesion Severity (CAILS) score in both MRG-106-treated and saline-treated lesions. The maximal reduction was on average 55% [range: 33% to 77%] in the MRG-106 treated lesion and 39% [range:13% to 75%] in the saline treated lesions). In all the subjects that completed dosing, the MRG-106 treated lesions had a CAILS score reduction of ≥ 50% which was maintained to the end of study; in contrast, a ≥ 50% reduction was observed in only one saline treated lesion. Most patients noted a marked decrease in systemic pruritus. Histological examination of pre-treatment and post-treatment biopsies of the same lesion injected with MRG-106 from five evaluable patients revealed that one patient had a complete loss of the neoplastic infiltrate, two patients had a reduction in neoplastic cell infiltrate density and depth, one patient had fewer CD30+ large atypical cells, and one patient demonstrated no change. After the first dose, MRG-106 had a mean t1/2 in plasma of 4.4 hours, and a mean Cmaxof 1.4 µg/mL. The drug was detectable 24 hours after the last dose in the MRG-106-injected lesions that were biopsied. Gene expression analysis of the pre- and post-treatment biopsies showed transcript changes consistent with the expected mechanism of action of MRG-106. Conclusions: These promising preliminary results in this first-in-human study in 6 MF patients show that intratumoral injection of MRG-106 was well-tolerated, and demonstrated encouraging therapeutic improvements in cutaneous lesions, based on CAILS scores and histological findings. In addition, reductions in CAILS scores in other lesions as well as decreases in systemic symptoms such as pruritus were observed. Preliminary biomarker analysis indicates that MRG-106 induces transcriptional changes consistent with on-target activity and molecular proof of concept. The trial is ongoing and additional results will be presented as available. Disclosures Querfeld: Actelion: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foss:Seattle Genetics: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Halwani:Bristol-Myers Squibb: Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Research Funding; Kyowa Hakko Kirin: Research Funding; Immune Design: Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Seto:miRagen: Employment. Ruckman:miRagen Therapeutics, Inc: Employment. Landry:Accera, Inc: Consultancy; miRagen: Consultancy. Jackson:miRagen: Employment. Pestano:miRagen Therapeutics: Employment. Dickinson:miRagen Therapeutics: Employment. Sanseverino:miRagen Therapeutics: Employment. Rodman:Nivalis: Employment, Equity Ownership; miRagen Therapeutics: Consultancy. Gordon:GLPI: Consultancy, Equity Ownership; IGM: Consultancy; Globavir: Consultancy; Pre-cell: Consultancy; Industrial Laboratories: Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy; Flugen: Consultancy; Bayer: Consultancy; miRagen Therapeutics: Consultancy; Clinipace: Consultancy; Caring for Colorado Foundation: Membership on an entity's Board of Directors or advisory committees; Ruesch Center for the Cure of Gastrointestinal Cancer: Membership on an entity's Board of Directors or advisory committees; Axion: Membership on an entity's Board of Directors or advisory committees; TEQ laboratories: Membership on an entity's Board of Directors or advisory committees. Marshall:miRagen Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: inventor on various patents; BiOptix: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fluorofinder: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AmideBio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Colorado BioScience Association: Membership on an entity's Board of Directors or advisory committees; Atlas Venture: Consultancy.

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Integrated Analysis of Global DNA Methylation and Transcription Reveals a Leukemia Subtype with Extreme Hypermethylation Associated with Silencing of Regulators of Differentiation

Blood ◽

10.1182/blood-2018-99-118521 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2608-2608

Author(s):

Claudia Gebhard ◽

Roger Mulet-Lazaro ◽

Lucia Schwarzfischer ◽

Dagmar Glatz ◽

Margit Nuetzel ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Promoter Methylation ◽

Research Funding ◽

Promoter Hypermethylation ◽

Ctcf Binding ◽

P Value ◽

Global Dna Methylation ◽

Employment Equity ◽

Equity Ownership

Abstract Acute myeloid leukemia (AML) represents a highly heterogeneous myeloid stem cell disorder classified based on various genetic defects. Besides genetic alterations, epigenetic changes are recognized as an additional mechanism contributing to leukemogenesis, but insight into the latter process remains minor. Using a combination of Methyl-CpG-Immunoprecipitation (MCIp-chip) and MALDI-TOF analysis of bisulfite-treated DNA in a cohort of 196 AML patients we previously demonstrated that (cyto)genetically defined AML subtypes, including CBFB-MYH11, AML-ETO, NPM1-mut, CEBPA-mut or IDH1/2-mut subtypes, express specific DNA-methylation profiles (Gebhard et al, Leukemia, 2018). A fraction of AML patients (5/196) displayed a unique abnormal hypermethylation profile that was completely distinct from any other AML subtype. These patients present immature leukemia (FAB M0, M1) with various chromosomal aberrations but very few mutations (e.g. no IDH1/2, KRAS, DNMT3A) that might explain the CpG island methylator phenotype (CIMP) phenotype. The CIMP patients showed high resemblance with a recently reported CEBPA methylated subgroup (Wouters et al, 2007 and Figueroa et al, 2009), which we confirmed by MCIp-chip and MALDI-TOF analysis. To explore the whole range of epigenetic alterations in the CIMP-AML patients we performed in-depth global DNA methylation and gene expression analyses (MCIp-seq and RNA-seq) in 45 AML and 12 CIMP patients from both studies. Principle component analysis and t-distributed stochastic neighbor embedding (t-SNE) revealed that CIMP patients express a unique DNA-methylation and gene-expression signature that separated them from all other AMLs. We could discriminate promoter methylation from non-promoter methylation by selecting MCIp-seq peaks within 3kb around TSS. Promoter hypermethylation was highly associated with repression of genes (PCC = -0.053, p-value = 0.00075). Hypermethylation of non-promoter regions was more strongly associated with upregulation of genes (PCC = 0.046, p-value = 4.613e-06). Interestingly, differentially methylated regions also showed a positive association with myeloid lineage CTCF binding sites (27% vs 18% expected, p-value < 2.2e-16 in a chi-square test of independence). Methylation of CTCF sites causes loss of CTCF binding, which has been reported to disrupt boundaries between so-called topologically associated domains (TADs), allowing enhancers located in a particular TAD to become accessible to genes in adjacent TADs and affect their transcription. Whether this is the case is under investigation. In this study we particularly focused on the role of hypermethylation of promoters in CIMP-AMLs. Promoters of many transcriptional regulators that are involved in the differentiation of myeloid lineages of which several are frequently mutated in AML were hypermethylated and repressed, including CEBPA, CEBPD, IRF8, GATA2, KLF4, MITF or MAFB. Notably, HMGA2, a critical regulator of myeloid progenitor expansion, exhibited the largest degree of CIMP promoter hypermethylation compared to the other AMLs, accompanied by a reduction in gene expression. Moreover, multiple members of the HOXB family and KLF1 (erythroid differentiation) were methylated and repressed as well. In addition, these patients frequently showed hypermethylation of many chromatin factors (e.g. LMNA, CHD7 or TET2). Hypermethylation of the TET2 promoter could result in a loss of maintenance DNA demethylation and therefore successive hypermethylation at CpG islands. We carried out regulome-capture-bisulfite sequencing on CIMP-AMLs compared to other AML samples and normal blood cell controls and confirmed methylation of the same transcription and chromatin factor promoters. We conclude that these leukemias represent very primitive HSCPs which are blocked in differentiation into multiple hematopoietic lineages, due to the absence of regulators of these lineages. Although the underlying cause for the extreme hypermethylation signature is still subject to ongoing studies, the consequence of promoter hypermethylation is silencing of key lineage regulators causing the differentiation arrest in these cells. We argue that these patients may particularly benefit from therapies that revert DNA methylation. Disclosures Ehninger: Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

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A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.2719.2719 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2719-2719 ◽

Cited By ~ 2

Author(s):

Luhua Wang ◽

Luis Fayad ◽

Fredrick B. Hagemeister ◽

Sattva Neelapu ◽

Felipe Samaniego ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Progression Free Survival ◽

Phase 2 ◽

Employment Equity ◽

Mantle Cell ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.1959.1959 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1959-1959 ◽

Cited By ~ 4

Author(s):

Jatin J Shah ◽

Jeffrey A. Zonder ◽

Adam Cohen ◽

Donna Weber ◽

Sheeba Thomas ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Clinical Activity ◽

Employment Equity ◽

Heavily Pretreated ◽

Equity Ownership ◽

Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

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Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽

10.1182/blood.v118.21.814.814 ◽

2011 ◽

Vol 118 (21) ◽

pp. 814-814 ◽

Cited By ~ 8

Author(s):

Paul G. Richardson ◽

Melissa Alsina ◽

Donna M. Weber ◽

Steven E. Coutre ◽

Sagar Lonial ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Treatment Phase ◽

Employment Equity ◽

Advisory Committees ◽

Overall Response ◽

Equity Ownership ◽

Grade 3 ◽

Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

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Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽

10.1182/blood.v118.21.602.602 ◽

2011 ◽

Vol 118 (21) ◽

pp. 602-602 ◽

Cited By ~ 3

Author(s):

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Neil Shah ◽

Dale Bixby ◽

Michael J. Mauro ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 1 ◽

Chronic Phase ◽

Hematologic Malignancies ◽

Employment Equity ◽

Advisory Committees ◽

Mutation Status ◽

Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. 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; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

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An Open-Label, Phase 1 Study of R-CVP in Combination with Inotuzumab Ozogamicin in Patients with CD22-Positive B-Cell Non-Hodgkin's Lymphoma: Preliminary Safety and Efficacy Data

Blood ◽

10.1182/blood.v120.21.1633.1633 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1633-1633

Author(s):

Michinori Ogura ◽

Kiyohiko Hatake ◽

Andrew Davies ◽

Michael Crump ◽

Kensei Tobinai ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Efficacy Data ◽

Inotuzumab Ozogamicin ◽

Advisory Committees ◽

Common Grade ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1633 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (NHL). This phase 1 study was conducted to identify the maximum tolerated dose (MTD) of INO when given in combination with R-CVP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.4 mg/m2 all on Day 1 and prednisone 40 mg/m2on Days 1–5) every 21 days, and to obtain preliminary safety and efficacy data for this regimen. Patients and methods: The study enrolled patients with relapsed/refractory CD22+ B-cell NHL. The dose-escalation part (Part 1; previously presented) identified the MTD as INO 0.8 mg/m2 given on Day 2 with R-CVP q3wks [Blood. 2011;118:3715]. Subsequent cohorts included the MTD confirmation cohort (Part 2) and MTD expansion cohort (Part 3), for collection of additional safety and preliminary efficacy data. Untreated patients who were not candidates for anthracyclines were allowed in Part 2 and Part 3 of the study. In Part 2 (n = 10), confirmation of the MTD required a dose-limiting toxicity (DLT) rate of <33% in Cycle 1 and fewer than 1/3 of patients discontinuing prior to Cycle 3 due to an adverse event (AE). In Part 3 (n = 22), additional patients were enrolled to explore preliminary signs of activity of INO when given in combination with R-CVP. Results: In Parts 2 and 3, a total of 32 patients with follicular lymphoma (FL; n = 15), diffuse large B-cell lymphoma (DLBCL; n = 16), or mantle cell lymphoma (n = 1) were enrolled. CD22 expression was confirmed by immunohistochemistry or flow cytometry prior to enrollment. The median age was 65 years (range, 44–81 years); 34% of patients had 1 prior anti-lymphoma regimen, 34% had 2, 28% had ≥3, and 3% (n = 1) had no previous therapy (median, 2; range, 0–6). The median number of cycles received was 5 (range, 1–6). In Part 2, the MTD was confirmed as standard-dose R-CVP plus INO 0.8 mg/m2, with 2 of 10 patients presenting with a DLT (grade 3 increase in alanine/aspartate aminotransferases [ALT/AST] and grade 4 neutropenia requiring granulocyte-colony stimulating factor). Four patients discontinued due to AEs after 2 cycles (n = 1), 3 cycles (n = 2), and 5 cycles (n = 1), respectively. Across Parts 2 and 3, the most common treatment-related AEs (all grades) were thrombocytopenia (78%), neutropenia (66%), fatigue (53%), constipation (50%), leukopenia (50%), and nausea (41%); the most common grade 3/4 AEs included neutropenia (63%), thrombocytopenia (53%), leukopenia (38%), lymphopenia (31%), increased ALT (9%), increased AST (6%), and febrile neutropenia (6%). There was 1 case of treatment-related fatal pneumonia associated with grade 4 neutropenia. Ten patients discontinued study treatment due to AEs, with thrombocytopenia or delayed recovery from thrombocytopenia being the leading AE causing study drug discontinuation (n = 9 [grade 1/2, n = 6; grade 3/4, n = 3]). The best overall response (ORR; partial + complete response [CR]) from Part 2 and 3 (31 evaluable patients) was 77% (n = 24/31), including 29% (n = 9/31) with CR. Of patients with FL, the ORR was 100% (n = 15/15), including 53% (n = 8/15) with CR. Of patients with DLBCL, the ORR was 60% (n = 9/16), including 7% (n = 1/16) with CR. Conclusions: Results from this phase I study showed that R-CVP in combination with INO 0.8 mg/m2 may have acceptable toxicity and promising activity in patients with relapsed or refractory CD22+ B-cell NHL, based on the response rates in FL and DLBCL. The most common grade 3/4 AEs were hematological toxicities, notably thrombocytopenia and neutropenia. Follow-up for progression-free survival and overall survival is currently ongoing; however, the observed results warrant additional study in both indolent and aggressive B-cell NHL. Disclosures: Ogura: Pfizer Inc: Research Funding. Hatake:Pfizer Inc: Research Funding. Davies:Pfizer Inc: Research Funding. Crump:Pfizer, Celgene, Roche, Millennium, Seattle Genetic: Membership on an entity's Board of Directors or advisory committees. Tobinai:Merck, Zenyaku, Symbio, Biomedics, Pfizer, GSK, Chugai/Roche: Research Funding. Smith:Pfizer Inc: Research Funding. Offner:Pfizer Inc: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. MacDonald:Roche Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Ex Vivo Pharmacologic Modulation in a Nutrient-Rich Medium to Accelerate Engraftment of Human Umbilical Cord Blood

Blood ◽

10.1182/blood.v124.21.3807.3807 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3807-3807

Author(s):

Corey S Cutler ◽

Daniel Shoemaker ◽

Peter Westervelt ◽

Daniel R. Couriel ◽

Sumithra Vasu ◽

...

Keyword(s):

Gene Expression ◽

Umbilical Cord Blood ◽

Ex Vivo ◽

Phase 1 ◽

Fold Increase ◽

Phase 2 ◽

Employment Equity ◽

Phase 2 Trial ◽

Equity Ownership ◽

Neutrophil Engraftment

Abstract Umbilical cord blood (UCB) offers many potential advantages as a source of hematopoietic stem cells (HSCs) for allogeneic transplantation, including ease of collection, rapid availability, flexibility of HLA-matching, lower rates of GvHD and potentially lower relapse rates. However, the low HSC content of UCB compared to other graft sources results in a prolonged time to engraftment, and higher rates of graft failure and early mortality. Pulse ex vivo exposure of HSCs to 16,16-dimethyl PGE2 (FT1050) has been demonstrated to enhance HSC engraftment potential, which could benefit clinical UCB transplant. FT1050 modulation promotes multiple mechanisms, including increased proliferation, reduced apoptosis, and improved migration and homing [North 2007&2009; Hoggatt 2009]. Improved HSC homing is mediated by induction of CXCR4 gene expression leading to increased cell surface CXCR4. Further optimization of the UCB modulation process demonstrated that incubation with 10µM FT1050 for 2 hrs at 37C resulted in a maximal biological response of the FT1050-UCB (ProHema®). A Phase 1 trial was performed to evaluate the safety of FT1050-UCB paired with an unmanipulated UCB unit in reduced-intensity double UCBT (dUCBT) [Cutler 2013]. We observed durable, multi-lineage engraftment of FT1050-UCB with acceptable safety. Earlier neutrophil engraftment was observed relative to historical controls (median 17.5 vs. 21 days (historical control), p=0.045), coupled with preferential engraftment of the FT1050-UCB unit in 10 of 12 subjects. A Phase 2 multi-center clinical trial of FT1050-UCB in adult patients undergoing dUCBT for hematologic malignancies was then initiated. Subjects are randomized 2:1 to FT1050-UCB-containing vs. standard dUCBT after high-dose conditioning. The primary endpoint is a categorical analysis of neutrophil engraftment using a pre-specified control median. Data on the initial 11 subjects, of which 8 were randomized to receive FT1050-UCB, continue to demonstrate acceptable safety with adverse events attributed to FT1050-UCB limited primarily to common infusion-related side effects. Of the 8 FT1050-UCB subjects, 1 died prior to neutrophil engraftment, with the remaining 7 subjects engrafting at a median of 28 days vs. 31 days for the 3 control subjects. With median overall follow-up of 16.1 months, 4 of 8 subjects on the FT1050-UCB arm are alive with a median survival not reached (> 11.0 months). 1 of 3 control subjects is alive with median survival of 6.0 months. During the clinical translation process, the media used during FT1050 modulation of UCB was identified as a key variable. Standard UCB washing media, consisting of a nutrient-free saline solution of low molecular weight dextran and human serum albumin (LMD/HSA), is used clinically to stabilize fragile cells post-thaw by reducing lysis. This media was used in the Phase 1 trial and to initiate Phase 2. Early during the Phase 2 trial, we identified a novel cell-stabilizing nutrient-rich formulation (NRM), containing glucose, amino acids and other HSC-supporting nutrients that promoted full FT1050 modulation of UCB and increased cell viability. The expression of key FT1050-pathway genes was significantly higher with NRM compared to intermediate levels observed with LMD/HSA. Modulation of human CD34+ (hCD34+) cells with FT1050 in NRM led to an 8-fold increase over LMD/HSA in induced CXCR4 gene expression (20-fold total), which translated to significantly increased surface CXCR4 protein. In vivo homing models demonstrated that UCB CD34+ cells modulated with FT1050 in NRM resulted in a 2.2-fold homing increase relative to vehicle (p < 0.001) compared to a 1.6-fold increase with LMD/HSA (p = 0.002), with a significant difference between the two media conditions (p = 0.04). A xenotransplantation study in NSG mice with hCD34+ cells modulated with FT1050 in either NRM or LMD/HSA demonstrated a 2-fold increase in circulating hCD45+ cells 12-weeks post-transplant with NRM (p = 0.007; unpaired t-test). These findings supported the incorporation of NRM into the FT1050-UCB manufacturing process in order to further improve its clinical engraftment potential. Enrollment of a 60-patient Phase 2 trial has been initiated that incorporates this manufacturing change. Disclosures Shoemaker: Fate Therapeutics: Employment, Equity Ownership. Rezner:Fate Therapeutics: Employment. Guerrettaz:Fate Therapeutics: Employment. Robbins:Fate Therapeutics: Employment. Medcalf:Fate Therapeutics: Employment. Wolchko:Fate Therapeutics: Employment, Equity Ownership. Ferraro:Fate Therapeutics: Employment. Multani:Fate Therapeutics: Employment.

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