Purpose Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. Patients and Methods Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. Results We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event–related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. Conclusion The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.
Although this regimen is toxic, it is active for patients ≤ 65 years of age and can be given both at academic centers and in experienced community centers.
A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30 min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3+3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and 2 patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.
Backround: Anti CD-20 radioimmunotherapy (RIT) is effective therapy for indolent B-cell NHL, and under investigation in more aggressive histologies. Most data on safety and efficacy of RIT is from the pre-rituximab era, and the effect of rituximab exposure on RIT in pts with NHL is unknown. Gopal et al recently demonstrated that exposure to rituximab correlated with inferior tumor response and alteration in tumor: organ dosimetry ratio both in vitro and in mouse models following therapy with iodine-131 tositumomab (Blood 112:830). Two ongoing SWOG trials evaluating RIT consolidation therapy provide a unique opportunity to evaluate the impact of prior rituximab on pharmacodynamics of iodine-131 tositumomab in humans. S0016 enrolls previously untreated pts with follicular NHL, and iodine-131 tositumomab consolidation is administered after 6 cycles of CHOP. S0433 enrolls previously untreated pts with DLBCL, and iodine-131 tositumomab is administered after 6 cycles of CHOP with rituximab, and 2 additional cycles of CHOP alone. As rituximab leads to B-cell depletion for 6 months or more, we hypothesized the residence time of iodine-131 tositumomab would differ in pts exposed recently to rituximab compared to no prior rituximab. Methods: Prospective pts at the University of Rochester enrolled in S0016 and S0433 were analyzed. Residence times of iodine-131 tositumomab were calculated using serial imaging on a Picker XP 2000 gamma camera. Rituximab levels were performed within one week prior to dosimetric iodine-131 tositumomab administration using ELISA. Medians were used to summarize the data, and the 2-tailed Mann-Whitney-Wilcoxon test was used for hypothesis testing. Results: 16 pts (6 female) on S0016 and 12 pts (6 female) on S0433, were identified, with median ages of 54.5 and 69.5 respectively. All pts had advanced stage disease, and median BMI and creatinine were similar for both groups. Pts on S0433 had a median time from rituximab to RIT of 78.6 days (range 58–98 days). Despite this, rituximab levels were present at time of iodine-131 tositumomab in all pts measured (N=9; median rituximab level 37.2 ug/ml, range 15.6–61.69). Median absolute lymphocyte count appeared lower in the S0433 group compared to the S0016 group (600 vs 1050 /ul), but this difference was not significant (p=0.12). Pts on S0433 (all had received rituximab prior to iodine-131 tositumomab consolidation) had significantly longer RIT residence times when compared to those on S0016, (not treated with prior rituximab): 115 hours vs. 107 hours; p=0.02. Therapeutic doses of iodine-131 tositumomab were not significantly different between the two studies (S0433: 72 mCi vs. S00016: 78 mCi p=0.59). Conclusions: Our results indicate that prior therapy with rituximab results in a longer residence time of iodine-131 tositumomab when used as consolidation after chemotherapy. Measurable rituximab levels at time of RIT suggest that rituximab-induced B-cell depletion decreases clearance of RIT, possibly allowing for longer exposure times. The significance of this longer residence time is unknown but it could be associated with greater toxicity to normal organs, and could be indicative of decreased tumor binding. If confirmed in larger studies, these findings could have profound implications on RIT administration in the context of rituximab. Rituximab-induced B-cell depletion could obligate the need for unlabeled antibody dosing prior to RIT, and may affect dosimetry of RIT. Prospective studies of RIT in the rituximab era should evaluate the impact of prior rituximab and RIT residence time on toxicities and outcomes in pts treated with RIT.
Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to promote cell death in various cancer cells, including malignant human hematopoietic cells. The novel, proteasome inhibitor carfilzomib is an attractive candidate for combination regimens due to diminished neurotoxicity, irreversible proteasome inhibition, favorable tolerability profile relative to bortezomib, and preclinical and clinical evidence of activity in bortezomib-resistant cells and patients. Preclinical studies demonstrated synergistic interactions between carfilzomib and vorinostat in human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells both in vitro and in vivo as well as in bortezomib-resistant cells (Dasmahapatra et al., Blood 115:4478; 2010; Mol Cancer Ther 10:1686, 2001). These preclinical findings prompted a phase 1 trial, using a 3+3 design, with the goal of determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for the combination of carfilzomib and vorinostat in patients with recurrent or refractory B-cell lymphomas. Eligible patients included those with recurrent or refractory non-Hodgkin’s lymphoma. The schedule of administration was vorinostat orally twice-daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Initial dose levels were 20/27 mg/m2 (carfilzomib) and 200 mg (vorinostat). To date, 20 patients have been treated at 4 dose levels. Patient characteristics included the following disease types: DLBCL, n = 6; follicular lymphoma, n = 2; MCL, n = 10; and transformed lymphoma, n = 2. The male to female ratio was 14:6, the median age was 67 years (range: 36-79), ECOG performance scores ranged from 0 to 2, and the median number of prior therapies was 3.5 (range: 1-13). Dose-limiting toxicities (DLTs) and adverse events were determined using CTCAE version 4. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment occurring in ≥ 5% of patients included anemia (grade 3, 15%), leukopenia (grade 4, 10%; grade 3, 15%), lymphopenia (grade 3, 10%), neutropenia (grade 4, 5%; grade 3, 25%), thrombocytopenia (grade 3, 10%), catheter-related infection (grade 3, 5%), dyspnea (grade 3, 5%), fatigue (grade 3, 5%), febrile neutropenia (grade 3, 5%), hypokalemia (grade 3, 5%), hyponatremia (grade 3, 5%), lymph node pain (grade 3, 5%), and pneumonitis (grade 3, 5%). Two grade 5 events were observed; 1 was attributed to disease progression and not related to study treatment; 1 was attributed to pneumonia possibly related to treatment. Common grade 2 AEs possibly, probably or definitely related to treatment in ≥ 15% of patients included anemia (25%), diarrhea (15%), fatigue (20%), hyperglycemia (15%), hypokalemia (15%), nausea (15%), neutropenia (15%), thrombocytopenia (20%), and vomiting (15%). There were 2 DLTs at dose level 1, grade 3 pneumonitis and febrile neutropenia, and there were no DLTs at dose level -1 (carfilzomib 20/20 mg/m2 and vorinostat 100 mg twice daily). Two intermediate dose levels (-1a and -1b) were added between dose-levels 1 and -1. No DLTs or significant differences in toxicities were observed at dose levels -1a and -1b. Consequently, two MTD/RP2D levels have been identified: carfilzomib 20/20 mg/m2 and vorinostat 200 mg twice daily (level -1a) and carfilzomib 20/27 mg/m2 and vorinostat 100 mg twice daily (level -1b). All 20 patients treated were evaluable for response. The best response on this phase 1 study was 1 partial response; 2 patients had stable disease. Correlative studies evaluating pre- and post-treatment plasma levels of IL-10 and TNF are currently undergoing analysis. Collectively, these findings indicate that the combination of carfilzomib and vorinostat is reasonably tolerable in this patient population. Two dose levels have been identified for the MTD/RP2D. The regimen appears to have modest activity in heavily pre-treated patients with relapsed and/or refractory B-cell lymphomas. Disclosures: Friedberg: Merck & Co.: Research Funding.
Background Imexon is a 1-carboxamido-2-cyan-aziridine isomer investigated as an anti-cancer agent given its pro-oxidant properties. By binding reduced sulfhydryls leading to the accumulation of reactive oxygen species, imexon interferes with the endoplasmic reticulum and mitochondrial reduction-oxidation (redox) balance, inhibiting protein translation and cell growth and inducing apoptosis. Pre-clinical studies demonstrated activity across an array of tumor cells in vitro and increased activity amongst B-cell non-Hodgkin lymphomas (NHL). A partial response in a follicular lymphoma (FL) patient was observed in a previous phase I study. This phase II trial was initiated to further investigate the clinical activity of imexon in patients with relapsed or refractory NHL. Methods Histologically confirmed NHL, > 1 prior therapy, age≥18, ECOG performance status 0–2, measurable disease, signed informed consent, creatinine and bilirubin < 2.0 x IULN as well as G6PD > IULN were required. Patients were treated with imexon 1000 mg/m2 IV daily on days 1-5 of a 21 day cycle for up to 1 year. Messenger RNA analysis was performed on pre-treatment tumor specimens, evaluating 22 genes important for antioxidant enzyme expression, 16 genes previously associated with outcome in NHL as well as 4 immune cell surface markers. Included were 13 genes used to generate a redox signature score, previously demonstrated to correlate with NHL prognosis (Tome, Blood 2005). Results Twenty-two NHL patients [9 FL, 5 diffuse large B cell (DLBCL), 3 mantle cell, 2 transformed follicular, 2 chronic lymphocytic leukemia and 1 Burkitt] with a median age of 64 (range 43-92) completed a median of 2.5 (range 1-13) cycles of therapy. With a median number of 4 prior therapies, 9 patients had undergone a prior stem cell transplant, 10 had stage IV disease and 6 were refractory to prior therapy. Twenty patients were evaluable for response, 2 pts discontinued therapy during cycle 1 due to progressive disease and grade 5 sepsis respectively. Of the 20 evaluable patients, the overall response rate was 30% (6/20) with another 35% achieving stable disease. Responses were observed in 4 FL and 2 DLBCL pts. After a median follow-up of 7 months, the median progression free survival (PFS) was 2.4 mos (range, 0.6 to 19.1 mos) with a median PFS of 6.7 mos (range, 1.2 to 9.0 mos) in FL patients. The median overall survival has not been reached. Grade 3 and 4 toxicities consisted of anemia (7 pts), thrombocytopenia (2 pts), neutropenia (2 pts), sepsis (2 pts), vomiting (2 pts), pneumonia (2 pts), fatigue (2 pts), dehydration (2 pts) as well as hypokalemia, hyperuricemia, transient ischemic attack, increased creatinine, rash and urinary tract infection in 1 pt each. 13 pts had available pre-treatment tumor biopsies, 2 of which attained a partial response with therapy. Patients with a higher redox score were more likely to achieve an objective response (p=0.03). Further, individual genes most predictive of response included CD68, GPX1 and SOD2. Conclusions This is the first trial to demonstrate that targeting the cellular redox environment is a viable therapeutic strategy in NHL and may be particularly effective in FL. The side effect profile may lend imexon to rational combination studies. Lymphomas reliant on antioxidant defense enzymes for proliferation and survival may be more susceptible to redox directed therapy. Evaluation of antioxidant related gene expression as a predictive biomarker is warranted in future investigations of imexon and similar targeted agents. (NCT01314014) Disclosures: Barr: Seattle Genetics: Consultancy; Celgene: Consultancy. Off Label Use: Imexon; being investigated for use in Non-Hodgkin lymphoma. Schwartz:HTG Molecular Diagnostics: Employment. Dorr:Amplimed Corporation: Employment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.