A Multicenter, Open-Label, Phase I/II Study of FN-1501 in Patients with Advanced Solid Tumors.

BACKGROUND: FN-1501, a potent inhibitor of receptor FMS-like tyrosine kinase 3 (FLT3) and CDK4/6, KIT, PDGFR, VEGFR2, ALK, and RET tyrosine kinase proteins, has demonstrated significant in vivo activity in various solid tumor and leukemia human xenograft models. Anomalies in FLT3 have an established role as a therapeutic target where the gene has been shown to play a critical role in the growth, differentiation, and survival of various cell types in hematopoietic cancer and have shown promise in various solid tumors. An open-label, Phase I/II study (NCT03690154) was designed to evaluate the safety and PK profile of FN-1501 as monotherapy in patients (pts) with advanced solid tumors and relapsed, refractory (R/R) AML. METHODS: Pts received FN-1501 IV three times a week for 2 weeks, followed by 1 week off treatment in continuous 21-day cycles. Dose escalation followed a standard 3 + 3 design. Primary objectives include the determination of the maximum tolerated dose (MTD), safety, and recommended Phase 2 dose (RP2D). Secondary objectives include pharmacokinetics (PK) and preliminary anti-tumor activity. Exploratory objectives include the relationship between pharmacogenetic mutations (e.g., FLT3, TP53, KRAS, NRAS, etc.), safety, and efficacy; as well as an evaluation of the pharmacodynamic effects of treatment with FN-1501. Dose expansion at RP2D further explored the safety and efficacy of FN-1501 in this treatment setting. RESULTS: A total of 48 adult pts with advanced solid tumors (N = 47) and AML (N = 1) were enrolled at doses ranging from 2.5 to 226 mg IV three times a week for two weeks in 21-day cycles (2 weeks on and 1 week off treatment). The median age was 65 years (range 30-92); 57% were female and 43% were male. The median number of prior lines of treatment was 5 (range 1-12). Forty patients evaluable for dose-limiting toxicity (DLT) assessment had a median exposure of 9.5 cycles (range 1-18 cycles). Treatment-related adverse events (TRAEs) were reported for 64% of the pts. The most common treatment-emergent adverse events (TEAEs), defined as those occurring in ≥20% of pts, primarily consisted of reversible Grade 1-2 fatigue (34%), nausea (32%), and diarrhea (26%). The most common Grade ≥3 events occurring in ≥5% of pts consisted of diarrhea and hyponatremia. Dose escalation was discontinued due to DLTs of Grade 3 thrombocytopenia (N = 1) and Grade 3 infusion-related reaction (N = 1) occurring in 2 pts. The maximum tolerated dose (MTD) was determined to be 170 mg. CONCLUSIONS: FN-1501 demonstrated reasonable safety, tolerability, and preliminary activity against solid tumors in doses up to 170 mg. Dose escalation was terminated based on 2 DLTs occurring at the 226 mg dose level.

Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer.

PURPOSE: To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. METHODS: The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. RESULTS: GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. CONCLUSION: GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

Iron Chelation in Transfusion-Dependent Patients With Low- to Intermediate-1-Risk Myelodysplastic Syndromes: A Randomized Trial.

Background: Iron chelation therapy (ICT) in patients with lower-risk myelodysplastic syndromes (MDS) has not been evaluated in randomized studies. Objective: To evaluate event-free survival (EFS) and safety of ICT in iron-overloaded patients with low- or intermediate-1-risk MDS. Design: Multicenter, randomized, double-blind, placebo-controlled trial (TELESTO). (ClinicalTrials.gov: NCT00940602). Setting: 60 centers in 16 countries. Participants: 225 patients with serum ferritin levels greater than 2247 pmol/L; prior receipt of 15 to 75 packed red blood cell units; and no severe cardiac, liver, or renal abnormalities. Intervention: Deferasirox dispersible tablets (10 to 40 mg/kg per day) (n = 149) or matching placebo (n = 76). Measurements: The primary end point was EFS, defined as time from date of randomization to first documented nonfatal event (related to cardiac or liver dysfunction and transformation to acute myeloid leukemia) or death, whichever occurred first. Results: Median time on treatment was 1.6 years (interquartile range [IQR], 0.5 to 3.1 years) in the deferasirox group and 1.0 year (IQR, 0.6 to 2.0 years) in the placebo group. Median EFS was prolonged by approximately 1 year with deferasirox versus placebo (3.9 years [95% CI, 3.2 to 4.3 years] vs. 3.0 years [CI, 2.2 to 3.7 years], respectively; hazard ratio, 0.64 [CI, 0.42 to 0.96]). Adverse events occurred in 97.3% of deferasirox recipients and 90.8% of placebo recipients. Exposure-adjusted incidence rates of adverse events (≥15 events per 100 patient treatment-years) in deferasirox versus placebo recipients, respectively, were 24.7 versus 23.9 for diarrhea, 21.8 versus 18.7 for pyrexia, 16.7 versus 22.7 for upper respiratory tract infection, and 15.9 versus 0.9 for increased serum creatinine concentration. Limitations: The protocol was amended from a phase 3 to a phase 2 study, with a reduced target sample size from 630 to 210 participants. There was differential follow-up between treatment groups. Conclusion: The findings support ICT in iron-overloaded patients with low- to intermediate-1-risk MDS, with longer EFS compared with placebo and a clinically manageable safety profile. Therefore, ICT may be considered in these patients. Primary Funding Source: Novartis Pharma AG.

[A retrospective analysis of 84 adult patients with Evans syndrome in a single center].

OBJECTIVE: To evaluate the initial clinical characteristics, the response to treatment, and the outcome in adult patients with Evans syndrome. METHODS: The clinical data of 84 adult patients (20 males, 64 females) with Evans syndrome diagnosed at our center between 1984 and 2007 were retrospectively analyzed. RESULTS: The patients were followed up for a median duration of 17.5 (0.03 - 140) months. All the patients initially received intravenous steroids with or without intravenous immunoglobulin (IVIG). Forty-seven patients were treated with corticosteroids alone initially. Complete remission (CR) and partial remission (PR) were achieved in 38 of the patients, but 92.1% of them relapsed during a median follow-up of 12 months. Twenty-eight patients who were resistant to corticosteroids therapy or with severe bleeding were subsequently administered immunosupressive agents. CR and PR were obtained in 89.3% of them. Within a median follow-up of 8 months, 84% of these patients relapsed. CONCLUSIONS: Evans syndrome is a chronic and easy to recurrent disease, which is often refractory to conventional therapy. Treatment with combination agents might be a useful therapeutic approach to the patients.

Single nucleotide polymorphism in DNMT3B promoter and the risk for idiopathic thrombocytopenic purpura in Chinese population.

OBJECTIVE: Epigenetic changes in gene expression, including DNA methylation and histone modifications, might contribute to autoimmunity. DNA methylation is mediated by a family of DNA methyltransferases. Polymorphisms of the DNA methyltransferase 3B (DNMT3B) gene may influence DNMT3B activity on DNA methylation, thereby modulating the susceptibility to some diseases. The purpose of this study was to investigate the association between the single nucleotide polymorphism (SNP) in promoter of the DNMT3B gene and the risk for development of idiopathic thrombocytopenic purpura (ITP). METHODS: In this hospital-based case-control study, the DNMT3B SNP was genotyped in 201 patients with ITP and 136 healthy controls by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The C/C genotype was not detected in both the patients with ITP and the controls. In the controls, the frequencies of T/T and C/T genotypes and T and C alleles were 97.8%, 2.2%, 98.9%, and 1.1%, respectively. There was no significant difference in genotype and allele distribution between the patients with ITP and the controls (P = 0.745 and 0.747, respectively). No significant difference was observed in genotype and allele distribution between the two groups when stratified by the age. The similar results were shown among the four groups of patients with ITP: acute childhood, chronic childhood, acute adult, and chronic adult. CONCLUSION: This polymorphism was distributed similarly between the patients with ITP and the controls. It demonstrated that it may not be used as a stratification marker to predict the susceptibility to ITP, at least in the population of North China.

[Clinical analysis of 438 patients with essential thrombocythemia].

OBJECTIVE: To analyse the clinical feature and natural course of essential thrombocythemia (ET). METHODS: A retrospective analysis was conducted in ET patients treated in our hospital during May 1980 to December 2006. RESULTS: Four hundred and thirty eight patients (201 males and 237 females with a median age of 48 years) were diagnosed. Hemorrhage occurred in 101 cases (23.1%), thrombosis in 86 cases (19.6%), and both hemorrhage and thrombosis in 13 cases (3.0%). Splenomegaly occurred in 150 cases and hepatomegaly occurred in 60 cases. One hundred and forty-nine cases (34%) had no symptoms at diagnosis and 145 cases (33.1%) confirmed by routine blood tests due to other diseases. The median platelet count at diagnosis was 1000 x 10(9)/L [(533 -3740) x 10(9)/L]. Bone marrow biopsy was performed in 255 cases which showed mainly increase of enlarged mature megakaryocytes with hyper-lobulated nuclei and local proliferation of reticular fiber was revealed in 51 cases. JAK2V617F mutation was detected in 90(78.9%) of 114 patients studied. Karyotype analysis was performed in 180 cases and 6 (3.3%) had clonal chromosomal aberrations. Two hundred and sixty-one patients were followed up over 12 months with a median of 60 months (range from 12 to 300 months). Seventeen cases (6.5%) evolved into marrow fibrosis (MF) and one case into polycythemia vera (PV). One case evolved into PV 6 years and then MF 20 years after diagnosis of ET. Three cases developed acute monocyte leukemia (M5), myelodysplastic syndrome (MDS) and multiple myeloma (MM), respectively. CONCLUSIONS: ET is a chronic myeloproliferative disorder characterized predominantly by thrombocytosis and hemorrhage. The percentage of asymptomatic cases is high. The prognoses for most cases were good with a few cases may evolve into MF.

Health-related quality of life measured by the Short Form 36 in immune thrombocytopenic purpura: a cross-sectional survey in China.

OBJECTIVES: The aim of this study is to assess the quality of life (QoL) of Chinese adults with idiopathic thrombocytopenic purpura (ITP). METHODS: The Chinese (mainland) version of Medical Outcome Study SF-36 form (SF-36) Health Survey was used to measure health-related QoL of 236 adults with ITP in a cross-sectional study. RESULTS: Comparison of SF-36 subscores of patients with ITP with healthy individuals revealed the reduction of QoL in all of the eight SF-36 dimensions. The difference on statistical significance presented in six of eight dimensions of SF-36 including physical functioning (PF), role limitations due to physical problems, body pain, general health perception (GH), social functioning (SF), and role limitations due to emotional problems (RE) between the patients with ITP and the normal population (P < 0.01). The acute ITP group showed better scores in three dimensions including GH, energy/vitality, and RE than chronic ITP (P < 0.01). Meanwhile through classification with platelet count, three subgroups of patients also experienced significant differences in PF, GH, and SF from the eight dimensions. Age was a significant negative predictor of all eight dimensions other than the SF while current platelet count was a significant negative predictor of GH. Moreover, the treatment cost and family income also influenced the QoL scores. The subjective feeling of fear about bleeding had a detrimental impact on QoL. CONCLUSIONS: QoL was impaired in patients with ITP, especially in the acute patients. The platelet count and the feeling of fear about bleeding had a detrimental impact on QoL.

Angiogenesis and antiangiogenic therapy in hematologic malignancies.

Angiogenesis, the generation of new blood capillaries from preexisting blood vessels, is tightly regulated in the adult organism. Although many of the initial studies were performed on solid tumors, increasing evidence indicates that angiogenesis also plays an important role in hematologic malignancies. Overexpression of angiogenic factors in particular VEGF and bFGF in most hematologic malignancies may explain the increased angiogenesis found in these malignancies and correlate with poor prognosis as well as decreased overall survival. In this review, we focus on the current literature of angiogenesis and antiangiogenic therapy in hematologic malignancies, and finally describe advances and potential challenges in antiangiogenic treatment in hematologic malignancies.