A Phase 1 Study to Assess the Absolute Bioavailability and Safety of An Oral Solution of Decitabine In Subjects with Myelodysplastic Syndromes (MDS),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3801-3801 ◽  
Author(s):  
Bipin Mistry ◽  
Mark M Jones ◽  
Peter Kubiak ◽  
Guillermo Garcia-Manero ◽  
Mark R. Litzow ◽  
...  
Keyword(s):  
Oral Dose ◽  
Myelodysplastic Syndromes ◽  
Oral Bioavailability ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Absolute Bioavailability ◽  
Study Results ◽  
The Absolute ◽  
Secondary Mds

Abstract Abstract 3801 Purpose: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes. The aim of this study was to determine the absolute bioavailability and safety of a single oral dose of decitabine. Methods: This is an open-label, Phase 1, dose-escalation absolute bioavailability trial in which decitabine was administered orally on Cycle 1 Day 1, and followed by a 1-hour IV infusion of the currently approved regimen (20 mg/m2) on Cycle 1 Days 2–5. Serial blood samples for decitabine pharmacokinetic (PK) assessment were collected up to 6 h post-dosing during Cycle 1 on Days 1 and 2. Three subjects were recruited at each oral dose level of 30, 60, 120 and 240 mg. Subjects were evaluated for adverse events (AEs). Results: Study results are summarized in Table 1. Sixteen subjects were screened and 12 were enrolled. Nine subjects had de novo MDS and 3 had secondary MDS (IPSS score Int-2 = 6, Int-1 = 5, Low = 1). Following oral dose, Cmax was reached within 0.50 h (tmax) and after Cmax the plasma profile showed biphasic decline with terminal half-life ranging between 0.36 to 0.93 hr. Increase in oral dose did not result in proportional increase in Cmax and AUC. The PK parameters following oral doses showed very high variability. Based on comparison of dose normalized exposure, the absolute bioavailability ranged between 3.9 to 14.1% and increased proportionally with dose. The non-dose normalized bioavailabilities were calculated to find a dose at which mean oral bioavailability reaches ≥80% of the current IV regimen of 20 mg/m2. The non-dose normalized bioavailability ranged between 11.7 and 80.5% with highest oral bioavailability observed at 240 mg dose. The most common SAEs were pneumonia (n=4) and neutropenic fever (n=4). Five patients (41.7%) experienced diarrhea and nausea (all grades). Conclusion: The study demonstrates that the absolute bioavailability ranged between 3.9 and 14.1%. Oral decitabine was generally well tolerated at doses between 30–240 mg in MDS subjects and exhibited a safety profile similar to the profile following intravenous administration. The bioavailability and safety data may allow for further testing in the phase 2 setting. Disclosures: Mistry: Eisai Inc.: Employment. Jones:Eisai Inc.: Employment. Kubiak:Eisai Inc.: Employment. Garcia-Manero:Eisai Inc.: Research Funding. Litzow:Eisai Inc.: Research Funding. Mesa:Eisai Inc.: Research Funding. Tarassoff:Eisai Inc.: Employment. Cortes:Eisai Inc.: Research Funding.

scholarly journals Hematologic Malignancies Exhibit Selective Vulnerability to Inhibition of De Novo Pyrimidine Biosynthesis By AG-636, a Novel Inhibitor of Dihydroorotate Dehydrogenase in Phase 1 Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1570-1570
Author(s):  
Danielle Ulanet ◽  
Victor Chubukov ◽  
John Coco ◽  
Gabrielle McDonald ◽  
Mya Steadman ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Solid Tumor ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Cancer Cell Lines ◽  
Pyrimidine Biosynthesis ◽  
Employment Equity ◽  
Equity Ownership

Rapidly proliferating cells reprogram metabolism to support increased biosynthetic demands, a feature that can expose targetable vulnerabilities for therapeutic intervention. A chemical biology screen was performed in an effort to identify metabolic vulnerabilities in particular tumor subtypes, and revealed potent and selective activity of a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic origin. In contrast, cancer cell lines of solid tumor origin exhibited comparatively poor sensitivity. Evaluation of a lymphoma cell line panel demonstrated broad responsiveness to DHODH inhibition, independent of clinical subtype (e.g. ABC, GCB, double-hit). The on-target cellular activity of AG-636 was evaluated by examining the metabolic effects of AG-636 on cells and by evaluating the ability of extracellular uridine to rescue the effects of AG-636 on proliferation and viability. The metabolic changes incurred upon treatment of cells with AG-636 were consistent with a mechanism of action driven by inhibition of DHODH and de novo pyrimidine biosynthesis. Supraphysiologic concentrations of extracellular uridine rescued the effects of AG-636 on growth and viability as well as the effects on metabolism, further confirming on-target activity. The mechanistic basis for differential sensitivity to AG-636 was assessed by comparing the activity of the de novo pyrimidine biosynthesis and uridine salvage pathways in cancer cell lines of hematologic or solid tumor origin with similar proliferative rates. Differential response to AG-636 could not be attributed to varying abilities to utilize the de novo pyrimidine biosynthesis pathway or to salvage extracellular uridine. Real-time imaging of cells treated with AG-636, along with monitoring of extracellular uridine concentrations, demonstrated immediate effects on the viability of lymphoma cell lines in the setting of depleted extracellular uridine. In contrast, solid tumor cell lines were able to maintain growth for an additional period of time, suggestive of adaptive mechanisms to supply pyrimidine pools and/or to cope with nucleotide stress. The high in vitro activity of AG-636 in cancer cells of hematologic origin translated to xenograft models, including an aggressive, patient-derived xenograft model of triple-hit lymphoma and an ibrutinib-resistant model of mantle cell lymphoma in which complete tumor regression occurred. These studies support the development of AG-636 for the treatment of hematologic malignancies. A phase 1 study has been initiated in patients with relapsed/refractory lymphoma (NCT03834584). Disclosures Ulanet: Agios: Employment, Equity Ownership. Chubukov:Agios: Employment, Equity Ownership. Coco:Agios: Employment, Equity Ownership. McDonald:Agios: Employment, Equity Ownership. Steadman:Agios: Employment, Equity Ownership. Narayanaswamy:Agios: Employment, Equity Ownership. Ronseaux:Agios: Employment, Equity Ownership. Choe:Agios: Employment, Equity Ownership. Truskowski:Agios: Employment, Equity Ownership. Nellore:Aurigene Discovery Technologies: Employment. Rao:Firmus Laboratories: Employment, Equity Ownership. Lenz:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau. Cooper:Agios: Employment, Equity Ownership. Murtie:Agios: Employment. Marks:Agios: Employment, Equity Ownership.

scholarly journals High-Resolution Next-Generation Whole Genome Optical Mapping As a Novel Molecular Diagnostic Tool for Comprehensive Assessment of Structural Chromosomal Variations in Myelodysplastic Syndromes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5438-5438
Author(s):  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban-Bravo ◽  
Koji Sasaki ◽  
Rajyalakshmi Luthra ◽  
Hui Yang ◽  
...  
Keyword(s):  
High Resolution ◽  
High Throughput ◽  
Myelodysplastic Syndromes ◽  
De Novo Assembly ◽  
Research Funding ◽  
Array Cgh ◽  
De Novo ◽  
Comprehensive Assessment ◽  
Next Generation ◽  
Allele Fraction

INTRODUCTION Structural variants (SV) include copy number aberrations (CNA) and balanced chromosomal rearrangements. Knowledge of SVs is important for diagnosis and prognosis of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and can alter therapy in some cases. However, high-throughput identification for diagnostic use in a CLIA-certified laboratory is limited by the need for a combination of techniques to detect both CNA and balanced rearrangements. Karyotyping evaluates 20 metaphases from dividing cells. Fluorescence in situ hybridization (FISH) targets known SVs. Microarray is less sensitive and cannot detect balanced rearrangements. While exome sequencing has limited ability to detect medium-large SVs and those adjoining repetitive sequences. Next-generation optical mapping (OM) is a novel technique to identify SVs by de novo assembly of extremely long-read fluorescently labeled DNA sequences against a reference followed by serial imaging. We hypothesize that OM could potentially offer a single platform for identification of all SVs. METHODS High molecular weight DNA was isolated from fresh bone marrow mononuclear cells preserved in DMSO. Minimum number of cells required was 1 million. A minimum of 36 ng/dL was required based on initial validation studies using cell lines. Specific sequences across the entire genome were labeled using a direct labelling enzyme (DLE-1). The generated long chromosomal fragments underwent high-throughput high-resolution imaging of long chromosomal fragments resulting in >100X genome coverage on Saphyr system (Bionano Genomics, San Diego). Algorithms to convert images to molecules was followed by de novo assembly of genome maps with reference [hg38]. Chromosomal aberrations were identified by comparing to a reference dataset that includes 200 healthy controls that facilitates detection of all structural abnormalities at a resolution of > 500 bp. Only SVs not identified in the control sample database with recommended variant confidence scores and strong molecule support were considered. Insertions, deletions and duplications larger than 100 kbp were considered. Based on sensitivity studies performed using simulations, the level of detection (LOD) was ~95% for SVs with allele fraction of ~10%. The generated data was compared with results from karyotype, FISH and microarrays (results were blinded during analysis). RESULTS A total of 7 MDS samples with 17 previously known aberrations were selected: 4 with complex karyotype (CK) that included deletions, insertions and translocations [2-way such as t(9;11), 3-way: t(2;20;17)] leading to derivative chromosomes and 3 with normal karyotype (NK). All 7 samples successfully underwent DNA extraction with an average yield of 60 ng/dL. OM identified all SVs detected by karyotype/ array CGH. This included deletions, insertions and translocations. Sixteen of 17 SVs identified by karyotype alone were detected by OM. The only SV missed was der(7)add(7)(p13)add(7)(q32), noted in 3 of 20 (~15% cell fraction) metaphases. With this knowledge, upon re-review, SV was detectable in the raw data at an allele burden of 7.5%, which is below the assay's LOD. For the same reason, this SV was not identified by array CGH (assay detection level ~20%). OM identified multiple additional SVs not detected by conventional techniques. In 4 samples with CK, a total of 6 new SVs were noted. This included del(17p) [25% allele fraction] involving TP53 gene in one patient (pt) [Fig 1A]. Identification of TP53 loss in this MDS pt with concurrent TP53 mutation has important prognostic and therapeutic implications. A novel fusion t(1;12) FGGY-DUSP16 was identified in another pt [Fig 1B,C] along with 2.1 Mb chr(6) deletion and 114 Mb chr(16) duplication. In 3 samples with NK, OM detected additional deletion of chr(19) involving genes: TCF3, GNA11, MAP2K2, SH3GL1, MLLT1 in one pt. No additional SVs were found in remaining 2 NK samples. OM facilitated precise mapping of genomic co-ordinates of SVs, especially with complex rearrangements. The LOD from these samples was estimated at ~10% allele fraction. CONCLUSIONS High concordance between OM and conventional techniques provides proof-of-concept for potential use of OM technology as a single-platform for comprehensive assessment of all SVs (CNAs and balanced rearrangements) in MDS at a resolution comparable to standard-of-care assays without the need for cell culture. Figure 1 Disclosures Sasaki: Otsuka: Honoraria; Pfizer: Consultancy. Kantarjian:Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; BMS: Research Funding; Takeda: Honoraria. Bueso-Ramos:Incyte: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

scholarly journals A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach

2019 ◽  
Vol 8 (1) ◽  
pp. 91-102
Author(s):  
Xiaomin Wang ◽  
Jian Chen ◽  
Josephine Reyes ◽  
Simon Zhou ◽  
Maria Palmisano ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Phase 1 ◽  
Absolute Bioavailability ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
The Absolute

A phase I study to assess oral bioavailability of a novel oral soft gelatin capsule formulation of rigosertib (ON 01910.Na) under fasted and fed conditions in patients with myelodysplastic syndromes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3081-3081 ◽  
Author(s):  
Azra Raza ◽  
Rami S. Komrokji ◽  
Roserika Brooks ◽  
Jeffrey E. Lancet ◽  
Alan F. List ◽  
...  
Keyword(s):  
Oral Dose ◽  
Phase I ◽  
Oral Bioavailability ◽  
Phase I Study ◽  
Oral Formulation ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Gelatin Capsule ◽  
Capsule Formulation ◽  
Soft Gelatin Capsule

3081 Background: Rigosertib (ON 01910.Na) is a novel multikinase inhibitor, with selective cytotoxic effects on tumor cells without impact on normal cells. Rigosertib, administered as a 3-day continuous infusion, is now undergoing phase 3 evaluation in higher risk MDS patients refractory to hypomethylating agents. Here, we report the results of the effect of food on the absolute bioavailability of a novel rigosertib oral formulation (soft gelatin capsule) in MDS patients. Methods: This was a single-dose, three-treatment, three-period sequential design for studying the effects of food on the bioavailability of an immediate-release soft gelatin capsule formulation. The following dosing groups were tested in 12 patients: IV Dose 800 mg/m2 over 24 hours and oral dose 560 mg (2 x 280 mg capsules) under fasting and fed conditions. The oral dose was the recommended phase 2 dose, as reported previously (R.S. Komrokji et al., Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results. Blood 2011, 118:Abstract #3797). Plasma samples were collected pre-dose, and over 32 hours (IV dose) or 8 hours (oral dose) after dose initiation. Rigosertib plasma levels were analyzed by a validated LC/MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental analysis (WinNonlinÒ). Results: Rigosertib pharmacokinetic parameters are presented in the table below. The results of the present study demonstrate good oral bioavailability under fasting condition.Oral administration of rigosertib after a meal decreased Cmax and AUC by 77% and 61%, respectively, compared to fasting conditions. Conclusions: The results of this study support the potential for oral delivery of rigosertib, which could become a preferred therapy over a 3-day continuous intravenous infusion. [Table: see text]

scholarly journals Anti-Leukemia Effect of FF-10501-01, a Novel Inosine 5'-Monophosphate Dehydrogenase Inhibitor, in Advanced Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), Including Hypomethylating Agent (HMA) Failures

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3800-3800 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hui Yang ◽  
Zhihong Fang ◽  
Courtney DiNardo ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Leukemia Cell ◽  
Clinical Activity ◽  
Guanine Nucleotide ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis

Abstract Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in AML cell lines and in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Thirteen leukemia cell lines were studied, including 5 parental AML cell lines and their HMA-resistant derivatives (MOLM13, SKM1, HL60, TF1, and U937), and 3 other AML cell lines (KG1, HEL, and OCI-AML3). Cell proliferation was determined using trypan blue analysis. Flow cytometry was performed to detect drug-induced apoptosis and cell cycle analysis. High-performance liquid chromatography (HPLC) was performed to detect the intracellular concentrations of guanine nucleotides. Mycophenolic acid-treated cells were used as positive control. Effect of guanosine supplement on FF-10501-01 treatment was evaluated. Within 72 hours of treatment, FF-10501-01 inhibited proliferation of all 13 AML cell lines. The IC50 of FF-10501-01 ranged between 4.3 and 144.5 µM. MOLM13 was the most sensitive leukemia cell line, whereas the decitabine-resistant TF1 cell line was the most resistant. FF-10501-01-induced apoptosis was observed in all cell lines. Increased numbers of cells in G1 phase and decreased numbers in S phase were observed in MOLM13, SKM1 and TF1 cell lines treated with <100 µM FF-10501-01. Decreased intracellular concentrations of guanine nucleotides were observed in MOLM13 and SKM1 cell lines treated with 3 to 30 µM of FF-10501-01 for 24 hours. Proliferation was partially rescued after 72 hours of treatment with 3 µM guanosine and FF-10501-01 in MOLM-13, HL60 cells and their HMA-resistant derivatives. No treatment synergy was observed with the combination of FF-10501-01 with HMAs in MOLM-14 and HL-60 or their HMA-resistant cell lines. In summary, FF-10501-01 produced potent anti-proliferative and apoptotic effects on AML cell lines through inhibition of de novo guanine nucleotide synthesis. In view of these pre-clinical findings, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ³ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. Sixteen patients (12 AML, 4 MDS) have been enrolled in 5 dose cohorts (50 - 400 mg/m2 PO BID) for 14 days on/14 days off each 28-day cycle, including 8 M and 8 F. Median (range) values: age 75.3 yrs (59.1 - 88.6); bone marrow blasts for AML patients 40.5% (12 - 71), for MDS patients 10% (6 - 13), or 30% overall (6 - 71); and prior treatment regimens 2.5 (1 - 6). All patients relapsed from, or progressed on, prior HMAs. Mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A and/or MDM2 were present in 4/16 (25%) patients. The median number of FF-10501-01 cycles received to date is 1.5 (range 1 - 10). No DLTs or drug-related serious adverse events (AEs) have been observed and FF-10501-01 has been very well tolerated through 5 - 10 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related Gr 4 prolonged thrombocytopenia and Gr 4 prolonged neutropenia were reported in one patient at 200 mg/m2 BID. Two partial responses (PRs) have been achieved in 1 patient each at 50 and 100 mg/m2 BID after 3 cycles, 7 (50%) patients demonstrated long-term stable disease over 2 - 10 cycles, and 4 patients have remained on study drug through 5 - 10 cycles and are still ongoing. Updated safety and efficacy data, including PK/PD, will be presented at the meeting. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS. Preclinical activity was seen in multiple leukemia cell lines. In a Phase 1 trial, clinical activity with PRs, prolonged disease stabilization and a highly tolerable safety profile were observed. The Phase 2 expansion phase will be initiated soon. Disclosures DiNardo: Novartis: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Smith:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutic, Inc.: Employment. Madden:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

scholarly journals Potential Barriers to Clinical Trials of New Therapeutics for Myelodysplastic Syndromes: Wide Variation in Risk Definitions and Trial Enrollment Criteria

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4378-4378
Author(s):  
Andrew M. Brunner ◽  
Jacqueline S. Garcia ◽  
R. Coleman Lindsley ◽  
Gregory A. Abel ◽  
Donna S Neuberg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Phase 1 ◽  
Phase Iii ◽  
Pharmacological Intervention ◽  
Exclusion Criteria ◽  
Very High

Abstract Introduction: Myelodysplastic syndromes (MDS) are neoplasms characterized by cytopenias, high risk of leukemic progression, and poor overall survival. Chemotherapy for MDS is not curative, and no new drugs have been approved for the treatment of MDS in over a decade. Clinical trials should be considered at any time during the management of patients with MDS, but enrollment criteria may be barriers that limit accrual. In this study, we extracted MDS clinical trial data from clinicaltrials.gov, and compared study indications and characteristics, including inclusion and exclusion criteria. Methods: We identified MDS clinical trials via clinicaltrials.gov (accessed: April 16, 2018). Studies were included if they allowed "MDS," "Myelodysplastic syndromes," "Preleukemia," and/or "Myelodysplasia," based on the pre-defined 'related terms' criteria in the database. We included interventional studies open in the United States that were listed as recruiting or not yet recruiting, for adults (age 18-64) and older adults (age 65+). We excluded studies that were observational in nature, involved a transplant-based intervention, or did not use a pharmacological intervention. We coded inclusion and exclusion criteria based on those provided by study authors in the database. Results: 83 interventional clinical trials enrolling patients with MDS were identified. Studies started enrollment between 4/1/2013 and 3/27/2018, and anticipated reaching the primary objective between 5/1/2017 and 6/1/2025. The median planned study duration was 38 mo (range 10-95). In total, studies sought to enroll 8866 patients over 273 study-years; the median study enrollment estimate was 1.7 patients/month, or across all trials 247 patients/month. Clinical trials could be exclusive to MDS patients (n=28), include MDS patients and other myeloid malignancies e.g. AML (n=44), or include MDS patients and other cancers including solid tumors (n=11). For clinical trials exclusive to MDS, the total enrollment goal was 1966 patients over 96 study-years, with a median rate of 1.4 patients/month (range 0.3-13.2) or total of 63 patients/month across all studies. 33 trials were phase 1 studies, 17 were phase 1/2, 26 were phase II, 1 trial was phase 2/3, and 6 were phase III studies. The primary endpoint was typically MTD (n=50) or ORR (n=22), while 5 studies had an OS endpoint. Most trials specified "higher risk" MDS (n=44); 8 specified "lower risk" MDS and 31 allowed all MDS risk or did not specify risk (Figure 1). Lower risk MDS studies were all exclusive to MDS patients. Inclusion criteria related to MDS risk varied significantly according to whether a study was MDS-specific or not (p=0.021): 82% of MDS-specific trials had risk exclusions, compared to 72% of myeloid trials, and only 36% of trials open across cancers. Of 52 trials specifying MDS risk, 20 included IPSS criteria, 24 included IPSS-R criteria, and 27 had blast count criteria. Lower risk MDS criteria was variably defined as IPSS low or INT-1 disease (n=3), IPSS-R very low or low risk (n=1), IPSS-R VL, L, or intermediate risk (n=4), or blast counts < 5% (n=1), < 10% (n=2), or <20% (n=2). There were variations in the criteria for transfusion dependence, including 2 transfusion units in 8 weeks (n=3), 4 in 8 weeks (n=2), 2 in 4 weeks (n=2), 1 in 6 weeks (n=1), and 2 in 16 weeks (n=1). For higher risk MDS, criteria included IPSS INT-1, INT-2, or High risk (n=7), IPSS INT-2 or High risk (n=12), IPSS-R intermediate, high, or very high risk (n=12), or IPSS-R high or very high (n=9); blast counts were set at >5% (n=12) or >10% blasts (n=12). Most studies specified exclusion of CNS disease, even though CNS involvement is exceptionally rare in MDS. 43 trials excluded concurrent cardiovascular disease; most often (n=18) requiring 6mo since a cardiovascular event. 46 trials had language excluding concurrent cancers, including 4 that did not allow any prior cancer, and 17 required ³24mo disease free. Exclusions for prior cancers did not vary according to primary outcome (MTD or PK, vs ORR/OS, p=0.16). 20 of 56 studies with MTD or early outcomes (e.g. PK) required cancer-free intervals of ³1y, while 7 allowed concurrent cancers if not on active therapy. Discussion: Currently enrolling MDS clinical trials show significant variation in their inclusion and exclusion criteria. Heterogeneous definitions of basic entry criteria, such as the definition of higher- and lower-risk MDS, may cause barriers to enrollment. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Garcia:Celgene: Consultancy.

Randomized Open-Label Phase II Study of Decitabine in Patients with Low- or Intermediate-1 Risk Myelodysplastic Syndromes,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3812-3812
Author(s):  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
De Novo ◽  
Phase Ii Study ◽  
Refractory Anemia ◽  
Metabolic Inhibitor ◽  
Open Label ◽  
Improvement Rate

Abstract Abstract 3812 Background: Decitabine (DAC) is a hypomethylating agent indicated for the treatment of myelodysplastic syndromes (MDS). We hypothesized that low-dose subcutaneous (SC) schedules of DAC may be active and safe in patients with lower risk MDS. Methods: This randomized, open-label, multicenter phase II study evaluated 2 DAC regimens in patients with low- or intermediate-1 risk MDS: 20 mg/m2/day SC for 3 consecutive days every 28 days (Arm A) or 20 mg/m2/day SC every 7 days (on days 1, 8, and 15) for 21 days, followed by 7 days without DAC (Arm B). The aim was to determine clinical activity, safety, and tolerability of the 2 regimens. The primary objective was overall improvement rate (OIR), defined as complete remission (CR), partial remission (PR), marrow CR (mCR), or hematologic improvement (HI), measured at the end of each cycle using patient's best response according to International Working Group (IWG) 2006 criteria. Secondary objectives included safety, HI, transfusion independence, cytogenetic response, and overall survival (OS). The tertiary objective was change in DNA methylation. Treatment on study was for ≤1 year, but patients who had clinical benefit could continue DAC off protocol. Target enrollment was 80 patients. Categorical and continuous variables were compared using Fisher's exact test and 1-way ANOVA, respectively; survival was analyzed with Kaplan-Meier, Cox regression, and log-rank methods. Results: Sixty-seven patients were randomized at 5 sites when the trial terminated early after achievement of protocol-defined superiority. On Oct 12, 2009, the posterior probability of at least 95% was met that OIR to Arm A was superior to Arm B. Thus enrollment in Arm B was terminated on Oct 16, 2009. Arm A was terminated on Dec 2, 2009, based on sponsor review and confirmation of achievement of protocol-defined superiority. The mITT population comprised 65 patients (Arm A, n=43; Arm B, n=22). Overall mean age (SD) was 68 y (13), 69% men; 89% had de novo MDS, and median time since diagnosis was 3.6 months (range, 0, 118). 94% had ECOG performance status (PS) 0–1, 29% had IPSS low-risk classification, and 69% had normal baseline cytogenetics. Arms were balanced apart from having more men in Arm B (P =.01). Patients received a median 7.0 (range, 1, 13) cycles of therapy in Arm A and 5.5 (2, 16) in Arm B. At study end, OIR was 10/43 (23%; 7 CR, 3 HI) and 5/22 (23%; 1 mCR, 1 PR, 3 HI) for Arms A and B, respectively (95% CI of difference: -21.1, 22.1). For transfusion status, of patients who were RBC dependent at baseline, 6/17 (35%) in Arm A and 4/8 (50%) in Arm B became independent on study. Corresponding data for platelets were 3/4 (75%) and 1/4 (25%), respectively. Approximately 40% of patients in each arm who were RBC/platelet dependent at baseline became independent on study. Of patients who were RBC independent at baseline, 24/26 (92%) in Arm A and 11/14 (79%) in Arm B remained independent on study. Corresponding data for platelets were 34/39 (87%) and 17/18 (94%), respectively, and for patients who were RBC/platelet independent, 22/25 (88%) and 9/12 (75%), respectively. IPSS, age, time from MDS diagnosis, type of MDS, prior MDS therapy, baseline cytogenetics, and ECOG PS were similar and did not affect OIR, HI, or transfusion status. There were no cytogenetic responses. At 500 days follow-up, median OS had not been reached (Figure); there were 8 deaths (19%) in Arm A and 6 (27%) in Arm B (hazard ratio 1.5; 95% CI: 0.5, 4.5). Induction of hypomethylation was seen in patients in both arms. All patients experienced ≥1 treatment-emergent AE. The most frequent at least possibly drug-related AEs for Arms A and B, respectively, were neutropenia (28% vs 36%), anemia (23% vs 18%), thrombocytopenia (16% vs 32%), fatigue (19% vs 9%), and leukopenia (9% vs 27%). Drug-related AEs of grade ≥3 were mainly hematologic and reported in 17 patients (40%) in Arm A and 10 patients (46%) in Arm B. There were no deaths within the first 8 weeks on study. One patient (neutropenic sepsis) in Arm A and 2 patients (1 each of anemia and MDS) in Arm B died as a result of an AE; none were reported to be drug related. Conclusions: DAC 20 mg/m2/day SC is active and well tolerated in lower-risk MDS. The OIR was similar in both arms, but a 3-day regimen appears more favorable than a 3x per week regimen based on all efficacy and safety results and the statistical decision to terminate the study early based on Arm A superiority. Further studies with these regimens are warranted. Disclosures: Off Label Use: Dacogen is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Borthakur:Eisai: Research Funding. Faderl:Eisai: Research Funding. Stein:Eisai: Employment. Noble:Eisai: Employment. Kassalow:Eisai: Employment. Kantarjian:Eisai: Research Funding.

Remissions after Third Induction Chemotherapy for Primary Non-Responders with Acute Myeloid Leukemia (AML) Are Uncommon and Short-Lived

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2800-2800
Author(s):  
Sara Farshchi Zarabi ◽  
Steven M. Chan ◽  
Vikas Gupta ◽  
Dina Khalaf ◽  
Andrzej Lutynski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Palliative Care ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Cell Transplant ◽  
Advisory Committees ◽  
De Novo Aml

Abstract The outcome of adult patients with AML who are primary non-responders to two courses of induction chemotherapy is poor. However, the utility of a 3rd induction for a select subgroup of these patients is uncertain. Here, we evaluated the rates of response and survival after a 3rd course of induction chemotherapy for primary non-responders with AML. We identified 98 patients from the Princess Margaret Cancer Centre between May 1999 and March 2015 who were non-responders to induction and reinduction chemotherapy. No-response to re-induction chemotherapy was defined according to the Revised Recommendations of the International Working Group for AML (JCO, 2003) as patients who survived > 7 days post re-induction and had persistent AML in blood or bone marrow (>5%). Median age was 58.3 years [range: 20-76.6]. 50 (51%) were male. 2% had favorable, 18% normal, 18% intermediate, and 48% adverse cytogenetics. 50% had de novo AML, 23% had AML secondary to MDS or MPN, and 17% had therapy-related AML. Induction chemotherapy consisted of "7+3" (n =88), Nove-HiDAC (n=1), Flag-Ida (n= 2), or similar variants (n=7). Reinduction chemotherapy consisted of Nove-HiDAC (n=70), Flag-Ida (n=7), "7+3" (n=1) or other similar variants (n =20). No patients received the same regimen for both induction and reinduction. Of the 98 primary non-responders, 15 received a 3rd induction regimen, while the others received supportive/palliative care ± low-dose chemotherapy (57 pts), or a non-induction clinical trial (26 pts). Average age was 56.4 (sd: 12.9) for patients who received supportive/palliative care and 47.0 (sd: 17.5) for patients who received a 3rd induction (p=0.008). Other baseline characteristics including gender, cytogenetic risk, marrow blast count post 2nd induction, and time between 1st and 2nd induction, did not differ between patients who did and did not receive a 3rd induction. Time to 3rd induction was a median of 54 days [range:36-126] from the start of the 2nd induction. Of the 15 third inductions, 7 were clinical trials evaluating novel agents in combination with induction chemotherapy, while the other 8 were combinations of standard chemotherapeutics (Flag-Ida n=1), AMSA+HiDAC (n=2), Daunorubicin+ HiDAC (n=1), Nove-HiDAC (n=4). Of the 15 patients who received a 3rd induction, 3 (20%) achieved a CR following Nove-HiDAC and Flag-Ida or AMSA+HiDAC chemotherapy, where the Ara-C was given as continuous infusion. 1 patient underwent allogeneic stem cell transplant (SCT) approximately 3.7 months after 3rd induction and remains alive 4.6 years post CR. 2 patients relapsed 2.3 and 4.7 months post CR without having received alloSCT. None of the 12 other patients responded to the 3rd induction and none had prolonged aplasia. 2 of 15 (13%) died during 3rd induction. Among the 83 patients who did not receive a 3rdinduction, 1 achieved a CR after a phase 1 clinical trial (MDM2 inhibitor) and remains in CR 3.6 years following an alloSCT. For patients who survived the immediate post induction period and were discharged from hospital median overall survival from the start of the 2nd induction did not differ between patients who did and did not receive a 3rd induction (276 days [range: 78-1304] vs 181.5 days [range: 47-1855] respectively p= 0.14). Median duration of hospital stay (including subsequent admissions) was longer for patients receiving a 3rd induction compared to those who did not (94 days following start of the 2nd induction [range: 47-169] vs 57 days [range: 51-181], respectively;(p= 0.003)). In summary, remissions after 3rd inductions for primary non-responders are uncommon, and short-lived, suggesting that 3rd inductions should be considered with caution and only when an SCT strategy is in place. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schimmer:Novartis: Honoraria.

Phase 1 Results of FF-10501-01, a Novel Inosine 5'-Monophosphate Dehydrogenase Inhibitor, in Advanced Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), Including Hypomethylating Agent (HMA) Failures

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1640-1640 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hui Yang ◽  
Zhihong Fang ◽  
Hagop M. Kantarjian ◽  
Courtney D. DiNardo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Cell Lines ◽  
Dose Level ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Clinical Activity ◽  
Guanine Nucleotide ◽  
Bone Marrow Blast

Abstract Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Previous preclinical studies demonstrated potent anti-proliferative and apoptotic effects of FF-10501-01 on AML cell lines, including HMA-resistant derivatives, through inhibition of de novo guanine nucleotide synthesis. Therefore, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ≥ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. A total of 29 patients, 15M and 14F (23 AML, 6 MDS) have been treated in 7 dose cohorts (50 - 500 mg/m2 PO BID) for 14 days on and 14 days off, and 400 mg/m2 for 21 days on and 7 days off, each 28-day cycle. Median (range) values: age 75 yrs (59 - 88); baseline bone marrow blast counts for AML 34% (12 - 82), for MDS 10% (5 - 16), and overall 30% (5 - 82); and prior treatment regimens 2 (1 - 7). All patients relapsed from, or progressed on, prior HMAs. At baseline, mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A, NOTCH1, JAK2, IDH2, PTPN11, KRA, TP53, RUNX1, EZH2 and/or MDM2 were present in 13 of 29 (45%) of patients. Atrial fibrillation (Gr 2) was reported in 2 subjects at a dose of 500 mg/m2 BID. This met the definition of dose-limiting toxicity (DLT) and no further enrollment was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose level lower, 400 mg/m2 BID, and this cohort was expanded to 6 subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 14 days. FF-10501-01 has been very well tolerated through 24 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related thrombocytopenia, neutropenia and bone marrow aplasia (all Gr 4) were reported in 1 patient at 200 mg/m2 BID. The median number of FF-10501-01 cycles received to date is 2 (range 1 - 24). Partial remissions have occurred in 2 AML patients (50 and 100 mg/m2 BID) after 3 cycles, lasting for 5 and 24 cycles, respectively, with the higher dose patient still on study after 24 cycles. A total of 8/23 (34.8%) AML patients, including the 2 PRs, have attained stable disease (SD) control with no disease progression over 3 - 24 cycles. Three AML patients remain on study through 3, 23 and 24 cycles, respectively. A bone marrow complete response was achieved in 1 MDS patient treated at 400 mg/m2 BID after 1 cycle. Although the bone marrow blast counts have increased since, this patient remains stable and is still on therapy through 14 cycles. Three of 6 MDS patients (50%), including the marrow CR, attained SD control with no disease progression over 3, 14 and 14 cycles, and 2 remain on study through 3 and 14 cycles, respectively. FF-10501-01 was rapidly absorbed with mean Tmax of 2.74 hours and mean t1/2 of 4.05 hours. Drug exposure (AUC0-24 and AUCcourse) increased with dose in a near linear manner. Potent suppression of circulating xanthine monophosphate (XMP), a marker of IMPDH activity, has been observed following FF-10501-01 administration on Day 1 of Cycles 1 and 2 at dose levels of 50 mg/m2 BID and above. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS in patients who have failed or progressed on HMAs and with one or more baseline mutations in pathways known to be affected in AML and MDS. Preclinical activity was seen in multiple leukemia cell lines, including HMA-resistant derivatives. In a Phase 1 trial, clinical activity with a marrow CR, PRs, long-term disease stabilization (≥ 5 cycles) and a highly tolerable safety profile were observed. The Phase 2a expansion phase of the study is soon to begin. Disclosures DiNardo: Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Denton:Westat Corporation: Employment. Smith:Westat Corporation: Employment. Tiefenwerth:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

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