Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

Phase I Trial of Flavopiridol In Relapsed Myeloma: Brief Response In t(4;14) with Significant Neutropenia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1933-1933
Author(s):  
Craig C. Hofmeister ◽  
Mindy A Bowers ◽  
Seungsoo Lee ◽  
Mitch A. Phelps ◽  
Don M Benson ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Human Serum ◽  
Intravenous Infusion ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Intravenous Bolus ◽  
Continuous Intravenous Infusion ◽  
Relapsed Myeloma ◽  
Final Cohort

Abstract Abstract 1933 Introduction: A pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion is active in fludarabine-refractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in relapsed multiple myeloma. Flavopiridol is a novel anti-cancer agent that targets cyclin dependent kinases (CDK) including the CDK9/cyclin T complex (preventing activation of RNA polymerase II), downregulates Mcl-1 and other anti-apoptotic proteins, and induces mitochondrial permeability changes. Flavopiridol is highly protein bound when in human serum, compared to protein binding seen in fetal bovine serum. This difference helps to explain the previous lack of clinical activity of flavopiridol (Dispenzieri et al, Haematologica, 2006) that targeted plasma concentrations based on in vitro cytotoxicity. A novel schedule of administration was designed to achieve and maintain target plasma levels predicted to be active in chronic lymphocytic leukemia from preclinical studies performed in human serum: 30-minute intravenous bolus (IVB) followed by 4-hour intravenous infusion (IVB/CIVI). This schedule, given for four of six weeks, is highly active in fludarabine refractory chronic lymphocytic leukemia. Methods: This was a phase I 3×3 single arm (standard method) study for relapsed myeloma patients having received at least two prior therapies. Adequate organ function was required with creatinine < 1.5 mg/dL and total bilirubin < 2x IULN. Adequate hematologic parameters were required with Hb > 9 g/dL, ANC>1500, and platelets > 50K during screening unless attributable to the patient's underlying myeloma. Results: 15 patients (ages 49–81 y.o.) with relapsed myeloma were consented. Median number of prior therapies was 7 (3-12). At the time of study entry, 8 patients displayed a complex karyotype, 2 patients with 17p deletion by CD138-selected FISH, and one patient with t(4;14); 3 patients with karyotypic chr 13 deletion and 9 patients by FISH. At study entry, 7 patients had ISS stage 3 disease, 4 with stage 2, and 4 with stage 1. 5 patients were treated in cohort 1 (30 mg/m2 bolus/30 mg/m2 CIV), 3 patients in cohort 2 (30 mg/m2 bolus/50 mg/m2 CIV), and 7 patients in cohort 3 (50 mg/m2 bolus/50 mg/m2 CIV). Median number of cycles received was 1. No patients achieved a confirmed PR – two patients achieved a minor response by IMWG criteria (see figure). The one patient with near 50% response in his IgA myeloma was the only patient with a t(4;14), 13-, and tetraploid cytogenetics by FISH. Grade 3/4 toxicities were significant with grade 4 neutropenia (10 patients), diarrhea (6 patients), transaminitis (4 patients), thrombocytopenia (3 patients), and anemia (5 patients). The most common toxicities included neutropenia, diarrhea, and AST elevation. Two patients in the first cohort and 1 patient in the final cohort were replaced due to inability to complete the first cycle. Pharmacokinetic results and immunohistochemical staining results for cyclin-D1 and pRb will be presented at the meeting; cyclin-D1 overexpression has been linked to CDK-inhibitor response (Dai Y et al, Cell Cycle 2006). One patient is undergoing screening to complete the final cohort and complete response and toxicity data will be reported. Discussion: Flavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes significant neutropenia and diarrhea but objective clinical responses were uncommon. (ClinicalTrials.gov Identifier: NCT00112723). Disclosures: Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding.

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia

Cancer ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 916-924 ◽  
Author(s):  
Stefan Faderl ◽  
Kanti Rai ◽  
John Gribben ◽  
John C. Byrd ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

Safety and Efficacy Results from a Phase I Trial of Single-Agent Lumiliximab (Anti-CD23 Antibody) for Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2503-2503 ◽  
Author(s):  
John C. Byrd ◽  
Susan O’Brien ◽  
Ian Flinn ◽  
Thomas J. Kipps ◽  
Mark A. Weiss ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Patient Characteristics ◽  
Outpatient Setting ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Treatment Regimens

Abstract The CD23 antigen is expressed at high density on the cell surface of certain B-cell malignancies, including chronic lymphocytic leukemia (CLL). Lumiliximab (L-mab), a macaque-human chimeric anti-CD23 monoclonal antibody, has been reported to have antitumor activity against CLL in preclinical studies. In this Phase I multicenter study, the safety, efficacy, and pharmacokinetics of single-agent L-mab were evaluated in 46 patients with relapsed or refractory CLL. Therapy consisted of intravenous L-mab given as 6 regimens: (1) 125 mg/m2/wk for 4 weeks; (2) 250 mg/m2/wk for 4 weeks; (3) 375 mg/m2/wk for 4 weeks; (4) 500 mg/m2/wk for 4 weeks; (5) 500 mg/m2 for 3 doses during Week 1, then 500 mg/m2/wk during Weeks 2 to 4; and (6) 500 mg/m2 three times a week for 4 weeks. Patient characteristics were as follows: median age of 62 years (range 47 to 80 years), 93% Caucasian, 72% male, 54% fludarabine-refractory, 48% Rai stage III/IV, and 78% WHO Performance Status 1. At study entry, patients had progressive CLL after 1 to 13 prior treatment regimens (median = 4 prior regimens). Antibody infusions, administered over 2 hours in an outpatient setting, were well tolerated. Study-related adverse events (probable, possible, or unknown relationship to study treatment) were reported in 40 of 46 patients (87%). The majority of events were Grade 1 or 2; the most common were headache, constipation, nausea, and cough. Grade 3 or 4 study-related adverse events were reported in 7 of 46 patients (15%) and included neutropenia and dyspnea. Evidence of clinical activity consisted of reductions in absolute lymphocyte counts (ALC) and lymphadenopathy. Decreases in ALC were observed in 42 of 46 (91%) patients, and decreases ≥ 50% were observed in 11 of 40 (28%) patients enrolled at 375 mg/m2/week or higher. Of 37 patients evaluated for change in lymphadenopathy, reductions were observed in 22 (59%). Flow cytometry revealed that L-mab saturated CD23 sites on CLL cells at doses above 375 mg/m2/week without down regulating CD23 expression. These results suggest that single-agent L-mab can be administered safely with evidence of clinical activity in patients with heavily pretreated CLL. Ongoing clinical studies are assessing the potential of L-mab in combination with rituximab and fludarabine-based chemotherapy.

Clinical Efficacy of Lenalidomide in Fludarabine-Refractory Chronic Lymphocytic Leukemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3108-3108 ◽  
Author(s):  
Asher A. Chanan-Khan ◽  
Myron S. Czuczman ◽  
Swaminathan Padmanabhan ◽  
Michael J. Keating ◽  
Susan M. O’Brien ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Refractory Disease ◽  
Overall Response

Introduction: Fludarabine treatment has been shown to be beneficial for patients with Chronic Lymphocytic Leukemia (CLL), and fludarabine-based combinations may even further improve outcomes in patients with CLL. However, most CLL patients eventually become fludarabine refractory, a state which is associated with a relatively short survival. Treatment of fludarabine-refractory patients is challenging, with a median survival of about 10 months. Recently, 2 phase II clinical trials (Chanan-Khan et al. JCO 2006 and Ferrajoli et al. ASH 2006) demonstrated the clinical efficacy of lenalidomide, an immunomodulatory agent, in relapsed/refractory CLL patients. We conducted a subset analysis to examine the efficacy of lenalidomide in patients who are fludarabine refractory. Methods: All patients enrolled on the 2 phase II single agent lenalidomide clinical trials were evaluated and patients with fludarabine-refractory disease (progressed while on or within 6 months of fludarabine-based therapy) were assessed for clinical efficacy of lenalidomide. Lenalidomide was given orally either at 10 mg daily for 28 days followed by 5 mg increments every 28 days to a maximum dose of 25 mg or given at 25 mg on days 1–21 of each 28-day cycle. Response was assessed using the NCI-WG 1996 criteria. Results: A total of 80 patients were collectively enrolled in these clinical studies. Among these, 29 were identified to have fludarabine-refractory disease. Important clinical characteristics of these patients are reported in Table 1. The overall response rate in fludarabine-refractory patients was 34.5% (10/29). Complete remission was observed in 2 (6.8%) patients. Conclusion: Lenalidomide is a novel agent with immunomodulating properties demonstrating clinical efficacy in relapsed or refractory CLL patients. Interestingly, clinical responses to single agent lenalidomide were noted despite refractoriness to fludarabine (a subset of CLL patients with poor survival and limited therapeutic options). This observation of the clinical benefit of lenalidomide independent of responsiveness to prior fludarabine is encouraging and warrants further evaluation. Table 1 Ferrajoli et al. Chanan-Khan et al. Fludarabine-refractory (N=12) Fludarabine-refractory (N=17) ORR, overall response rate; PFS, progression-free survival; OS, overall survival. Median age, years (range) 62 (51–82) 68 (53–75) Sex, female/male 4/8 4/13 Median no. prior therapies (range) 4 (3–15) 4 (1–10) Median beta microglobulin (range) 5 (3–10) 5 (2–10) Advance Rai Stage (III/IV), n (%) 7 (58.3) 13 (76.4) ORR, n (%) 3 (25.0) 7 (41.2) Median PFS, months 12 14.9 Median OS, months All alive (range, 7–19) 23

scholarly journals Phase II trials of single-agent anti-VEGF therapy for patients with chronic lymphocytic leukemia

2010 ◽  
Vol 51 (12) ◽  
pp. 2222-2229 ◽  
Author(s):  
Tait Shanafelt ◽  
Clive Zent ◽  
John Byrd ◽  
Charles Erlichman ◽  
Betsy Laplant ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase Ii Trials ◽  
Anti Vegf

Phase I Study of Flavopiridol in Combination with Imatinib Mesylate (STI571, Gleevec) in Bcr/Abl+ Hematological Malignancies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1102-1102 ◽  
Author(s):  
Steven Grant ◽  
Judith E. Karp ◽  
Omer N. Koc ◽  
Brenda Cooper ◽  
Selina Luger ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Phase Ii Trials ◽  
Pronounced Increase ◽  
Dose Levels

Abstract Imatinib (Im), a rationally designed inhibitor of the Bcr/Abl kinase as well as other kinases, represents the standard treatment for Bcr/Abl+ malignancies. Im as a single agent, however, is not curative. Flavopiridol (Fl), an investigational cyclin dependent kinase inhibitor, is broadly active in vitro against human leukemia cells (Blood91:2482,1998). Previously we have shown that simultaneous disruption of a survival signaling pathway and a cell cycle regulatory pathway results in a pronounced increase in leukemic cell death (Cancer Res.61:5106,2001) and in more recent preclinical studies demonstrated synergistic interactions between Im and Fl in Bcr/Abl+ leukemia cells, including some that were resistant to Im (Clin Cancer Res8;2976,2002). Based on these considerations, we have initiated a phase I trial to identify appropriate doses of Im+Fl for further investigation. Eligible patients (pts) have CML with a suboptimal response to prior Im, CML in blast crisis, or Bcr/Abl+ acute lymphocytic leukemia (ALL). CML-BC and ALL patients may be Im-naïve. Pts receive Im by continuous daily oral dosing and Fl by 1 hour intravenous infusion weekly x 3 repeated every 4 weeks. Targeted dose levels are (Fl/Im; mg/m2): 30/400, 30/600, 45/600, 60/600, 60/800, 60/1000. Patients are divided into 2 strata based upon blast percentage in peripheral blood or bone marrow: stratum 1, &lt;15%; and stratum 2, ≥15%. For stratum 1 dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelet for &gt; 1 week or grade ≥ 3 non-heme toxicity; for stratum 2, DLT is profound marrow hypoplasia in the absence of persistent leukemia. In stratum 1, 16 pts have been treated at 4 dose levels; in stratum 2, 5 pts in the 1st and 3rd dose level. In stratum 1, 1 DLT has occurred at dose level 4 (cholecystitis requiring cholecystectomy); in stratum 2, 1 DLT has occurred at dose level 3 (sepsis/multi-organ failure which was not clearly related to treatment). The only frequent toxicities have been hematological. 4 pts have experienced objective responses including complete hematological remissions in 2 pts in stratum 1 treated with Im/Fl 30/600 who had been previously treated with Im 800 and complete hematological remissions in 2 pts in stratum 2 (who had not received prior Im). Preliminary studies indicate no Fl impact upon Im pharmacokinetics, and variable post-treatment effects on signaling pathways in CML cells. These findings indicate that a regimen consisting of Fl and Im is tolerable and active in at least some patients with Bcr/Abl+ hematologic malignancies, including some with Im-resistant disease. Pending identification of the MTD and the recommended Phase II dose (RPTD), Phase II trials will be necessary to assess the activity of this strategy more definitively.

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