scholarly journals Phase II Study of Targeted Subcutaneous (SC) Bortezomib for Patients with Low- or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndrome (MDS) with Evidence of NF-κB Activation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1930-1930
Author(s):  
Jasleen K. Randhawa ◽  
Kausar Jabeen Jabbar ◽  
Tapan Kadia ◽  
Gautam Borthakur ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Neuropathy ◽  
Phase Ii ◽  
Stable Disease ◽  
Lower Risk ◽  
Conflicts Of Interest ◽  
Phase Ii Study ◽  
Response To Therapy ◽  
Trisomy 8 ◽  
Transfusion Independence

Abstract Introduction: Alterations of innate immunity signaling and activation of NF-κB are known to occur in low/int-1-risk MDS (Braun, 2006, Wei, 2013). These suggest that modulation of NF-κB could be a therapeutic target in this group of patients. Bortezomib is a proteosome inhibitor with potential inhibitory activity against NF-κB. To determine whether bortezomib has therapeutic activity in lower-risk MDS patients, we designed a phase II trial of SC bortezomib in patients with lower-risk MDS and evidence of NF-κB activation. Methods: This was a single-arm phase II study of bortezomib in low/int-1-risk MDS patients. Bortezomib was administered at 1.3 mg/m2 SC on days 1, 4, 8, and 11 in a 21 day cycle for a maximum of 2 years of therapy. Eligibility criteria included age ≥18 years, adequate performance and organ function, and having received at least 1 prior therapy. Patients with grade 2 or greater peripheral neuropathy at baseline were excluded. Patients were then prescreened prospectively for enrollment by assessing cellular levels of the phosphorylated NF-κB subunit p65 (pp65) in their marrows. This was performed in bone marrow aspirate smears stained for immunofluorescence using an antibody against a phosphorylated form of NF-κB p65 (phospho-Ser276). This assay was performed in the Department of Hematopathology following CLIA regulations. Pp65 was considered positive if at least 5% of all the nucleated marrow cells were positive for pp65 staining. Subsequently, pp65 levels were assessed on day 21 of cycles 1 and 2 and then in subsequent marrows as clinically indicated. Responses were assessed according to IWG06. The study could accrue a maximum of 40 patients if there were at least a 95% chance of at least a 15% ORR. Results: Since 9/2013, we have enrolled 12 patients with a median age of 72 years (range 56 - 87). Median marrow blast percentage was 1.5% (range 1 – 5%). Nine patients had diploid cytogenetics, 2 had del 20q, and 1 had trisomy 8. All patients had low (2 patients) or int-1 (10 patients) disease. All were transfusion dependent (6 both platelets and red cells (PRBCs), 1 only platelets and 5 only PRBCs). Ten (83%) of the 12 had received prior hypomethylating agent (HMA) therapy. Thus far, patients have received a median of 3.5 cycles (range 1-12). Baseline median pp65 was 26.5% (range 7 – 70%). Five patients were taken off the study, 2 for disease progression and 3 for no response after a median of 3 cycles. Seven remain on study. No grade 3/4 toxicity and minimal grade 1/2 toxicity have been observed. No peripheral neuropathy has been observed. The median overall survival has not been reached. At a median follow up of 17 weeks, the overall response rate is 33% (3 HI-EP and 1 HI-N). Six patients have stable disease, and 2 had progression. One patient achieved red cell transfusion independence, going from PRBCs every 2 weeks to no transfusions after 2 cycles. All responders had been previously treated with an HMA. At day 21, the median pp65 level was 23% (0-70) and subsequently 22% (5-50) (all NS). Pp65 decreased by at least 50% in 5 patients, but it fell below 5% in only 2 patients. Two of the 5 patients with decreased levels of pp65 had a response to therapy. Of interest, the patient that achieved transfusion independence had a substantial decrease in pp65 (to less than 5%) that was lost (up to 56% pp65) when the patient lost hematological response. We also screened patients with a 28-gene mutation panel and found a MET, JAK2, or TET2 mutation in each of the 3 patients achieving a hematological improvement, a RUNX1 or CEBPA in each of the two patients with progressive disease, and an APC or ASXL1 mutation in each of the patients with stable disease. Conclusions: Bortezomib is well tolerated and results in hematological improvement in pretreated patients with lower-risk MDS. It is feasible to assess pp65 in serial bone marrow samples in this group of patients. Pp65 decreases in 40% of patients, and substantial decreases may be associated with response. This study suggests that it is possible to target patients for therapeutic intent using the NF-κB pathway as a biomarker. Disclosures No relevant conflicts of interest to declare.

scholarly journals Updated Phase II Study of Targeted Subcutaneous (SC) Bortezomib for Patients with Low- or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndrome (MDS) with Evidence of NF-κb Activation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3191-3191
Author(s):  
May Daher ◽  
Juliana Elisa Hidalgo Lopez ◽  
Jasleen K. Randhawa ◽  
Kausar Jabeen Jabbar ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Lower Risk ◽  
Research Funding ◽  
Phase Ii Study ◽  
Performance Status ◽  
Eligibility Criteria ◽  
Prior Therapy ◽  
Transfusion Requirements ◽  
Blast Count

Abstract Introduction MDS has been linked to constitutive activation of genes involved in the nuclear factor-kappaB (NF-κB) pathway [Wei et al. Leukemia 2013; Braun et al. Blood 2006]. Hence, NF-kB is an attractive therapeutic target in this disease. Bortezomib is a proteosome inhibitor with inhibitory activity against NF-κB. We designed a phase II trial of SC bortezomib in patients with low- to intermediate (low/int-1)-risk MDS and evidence of NF-κB activation to determine its therapeutic activity in these patients. Methods In this single-arm phase II study in low/int-1-risk MDS patients, bortezomib was administered at 1.3 mg/m2 SC on days 1, 4, 8, and 11 in a 21-day cycle for a maximum of 2 years of therapy. Eligibility criteria included age ≥18 years, adequate performance status and organ function, and having received at least 1 prior therapy. Patients with grade 2 or greater peripheral neuropathy at baseline were excluded. Patients were prescreened prospectively for enrollment by assessing cellular levels of the phosphorylated NF-κB subunit p65 (pp65) in their marrow. This was performed by immunofluorescence with phospho-Ser276 in bone marrow aspirate smears in the Department of Hematopathology (CLIA regulations). Patients were eligible if at least 5% of all nucleated marrow cells were positive for pp65 staining. pp65 levels were assessed again on day 21 of cycles 1 and 2 and then as clinically indicated. Responses were assessed according to IWG [Cheson et al. Blood 2000; Cheson et al, Blood 2006]. The study could accrue a maximum of 40 patients if there were at least a 95% chance of at least a 15% ORR. Results Beginning 9/2013, we enrolled 15 patients with a median age of 71 years (range 56 - 87). Median marrow blast percentage was 1.9% (range 0 - 5%). Eleven patients (73%) had diploid cytogenetics, 2 had del(20q), 1 had Y-, and 1 had del(5q). All had lower-risk MDS by IPSS (low 33.3%, int-1 66.7%). All were transfusion dependent (6 both platelets and red cells (PRBCs), 1 only platelets, 8 only PRBCs). Hypomethylating agents had failed in 12 of the patients. At a median follow-up interval of 22 weeks, the ORR was 20%; 3 patients had hematologic improvement with a mean duration of response of 14.3 weeks (range 4-21). Eight patients had stable disease, and 4 had progression. No correlation between clinical response and molecular or cytogenetic data was observed. Eventually, all patients were taken off study: 7 due to increasing transfusion requirements, 2 worsening cytopenia, 1 lack of response, 1 increased blasts, and 1 grade 2 neuropathy; 2 withdrew by choice, and 1 patient died from causes unrelated to the study. Four patients experienced ≥ 1 grade 3 toxicity. No grade 4 toxicity was observed. Seven patients experienced grade 1 (n=4) or grade 2 (n=3) neuropathy. Morphologic review (n=14) in the responders group (n=3) showed reduction in ring sideroblasts (RS) in 2 patients (60 to 47% and 43% to 30%). Two patients, including 1 of those with reduced RS, had improvement of dysplasia (from severe trilineage dysplasia to moderate bilineage dysplasia). No changes in cytogenetic studies were found in the responder group. Among nonresponders (n=11), 3 had new acquired cytogenetic abnormalities, 3 had worsening dysplasia, and 2 had increase in blast count (1% to 3% and 1% to 4%). Two had no morphologic changes during treatment. One showed improvement in dysplasia and blast count (2% to 0%) and no changes in cytogenetics. Interestingly, 3 nonresponders showed RS reduction during treatment (18% to 1%, 85% to 45%, and 6% to 0%). The median pp65 level at baseline was 30.87% (range 7 - 70%). The pp65 level decreased in 7 of the 15 patients (46.7%), in 6 of them by the end of cycle 1. Interestingly, the 3 responders were among the 7 patients who had a decrease in pp65 level. Eventual loss of response in these patients was accompanied by return to a higher pp65 level. In nonresponders, the pp65 level increased in 7, decreased in 2, and remained unchanged in 1; for 1, the sample was suboptimal. Conclusions In previously treated lower-risk MDS patients, SC Bortezomib was well tolerated and resulted in hematologic improvement and decrease in RS. NF-κB activation, measured by pp65 level, can be a useful biomarker to select patients with lower-risk MDS who could benefit from therapies that target this pathway. The NF-κB pattern of expression suggests an inverse relationship between treatment response and NF-κB level, with associated improvement in bone marrow morphology. Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Activity of Lenalidomide in a Phase II Single Institution Study in Non-Del(5q) Transfusion Dependent, Patients with Low and Intermediate-1 Risklower-Risk, Non-Del(5q) Myelodysplastic Syndromes (MDS))): Results From a Single-Institution Phase II Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4929-4929
Author(s):  
Azra Raza ◽  
John Falkenstern ◽  
Fiona Yeh ◽  
Ginevra Castagna ◽  
Antonietta De Los Reyes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Duration ◽  
Lower Risk ◽  
Conflicts Of Interest ◽  
Phase Ii Study ◽  
International Prognostic Scoring System ◽  
Clinical Activity ◽  
Single Institution ◽  
Hematologic Response ◽  
Grade 3

Abstract Abstract 4929 In a previous multi-center Phase II study, lenalidomide resulted in a 43% overall hematologic response with 26% of patients achieving transfusion independence (TI) among 214 non-del(5q) red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System (IPSS) lower-risk MDS (Raza et al Blood. 2008). A single institution follow-up trial was conducted in patients with low or Int-1 risk non-del(5q) MDS, a platelet count of >50, 000 and requiredat least 2 units of blood required in 8 weeks. Fifty-six patients received lenalidomide at a starting dose of 10 mg qday. There were 41 males and 15 females, and the median age was 71 years. By IPSS, 27 had low-risk disease and 22 had Int-1-risk disease, while IPSS could not be assigned for 7 patients. By cytogenetics, 38 patients had a normal karyotype, 12 showed abnormalities, while data could not be obtained for 4 patients due to culture failure. Morphologic classification consisted of: RA=17, RCMD=16, RARS=4, RCMD-RS=7, RARS-T=1 and RAEB-1=11. Median duration of MDS was 12 months (range 1–120 months). Median transfusion requirement was 2 units in 8 weeks prior to starting therapy. Median duration of lenalidomide therapy was 4 months (range, 1–36+ months). Treatment was generally well tolerated. The most common Grade 3/4 toxicity was myelosuppression, with 17 (30%) experiencing thrombocytopenia, 12/(21%) neutropenia and 1 leukopenia (2%). Other Grade 3/4 toxicities included diarrhea (7%) rash (2%), and fatigue (2%). At least one dose reduction was required for 33 (59%) patients. Intent-to-treat analysis showed hematologic response (HI) by the IWG-R criteria in 23 (41%) patients, no response in 25(44%) patients, and other failure in 8 (14%) patients. Among the 23 responders, 18 (32%) achieved TI. Median time to response was 2 cycles (6 weeks), with 6 patients responding in cycle 1, 9 in cycle 2, 5 in cycle 3 and 1 each in cycles 4, 5, 6, respectively. Median duration of response was 294 days (approximately 10 months), with durations ranging from 44+ days to 936+ days (+ indicates continuing response). We confirm in this 56-patient, single institution phase II study that lenalidomide has substantial clinical activity in transfusion-dependent, lower-risk non-del(5q) MDS, with results comparable to those previously reported in the multi-center phase II study. Disclosures: No relevant conflicts of interest to declare.

Thalidomide and Rituximab in Waldenström’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1484-1484 ◽  
Author(s):  
Andrew Branagan ◽  
Zachary Hunter ◽  
Daniel Ditzel Santos ◽  
Steven P. Treon
Keyword(s):  
Phase Ii ◽  
Cumulative Dose ◽  
Stable Disease ◽  
Phase Ii Study ◽  
Response Rates ◽  
Response To Therapy ◽  
Major Response ◽  
Grade 3 ◽  
Thalidomide Analogue ◽  
Dose Modifications

Abstract Rituximab and thalidomide are active agents in Waldenstrom’s macroglobulinemia (WM) producing major response rates of 25–50%. Moreover, as previously shown by us, thalidomide enhances rituximab mediated ADCC killing of lymphoplasmacytic cells (Blood 100:314b). As such, we conducted this phase II study using combination rituximab and thalidomide in WM patients who previously had not received rituximab or thalidomide. Intended therapy was as follows: Weeks 1–52 Thalidomide (200 mg po qhs for 2 weeks, then 400 mg po qhs) Weeks 2–5 Rituximab (375 mg/m2/week) Weeks 13–16 Rituximab (375 mg/m2/week) Patients were evaluated at week 12, and if they had at least stable disease (SD) were eligible for further therapy and for response evaluation. Dose modifications, delay, and/or discontinuation of thalidomide were permitted for toxicities. Twenty-five patients have been enrolled, 20 of whom were previously untreated. Six patients are off study, 4 because of no response and 2 because of deaths unrelated to protocol therapy. Grade 3/4 toxicities to thalidomide included neuropathy (n=15); somnolence or confusion (n=12); rash (n=7); tremors (n=2); bradycardia (n=2); other (n=3); and led to its eventual discontinuation in 11/19 patients. All evaluable patients received the intended rituximab therapy. Paradoxical IgM spikes following rituximab occurred during both courses of therapy and were observed in 12/25 (48%) patients similar to those spikes which we reported with rituximab monotherapy (ASH2003; 102:690a). Responses to date among the 23 evaluable patients are as follows: CR (n=1); PR (n=12); MR (n=2); SD (n=4). Four patients had no response to therapy. No patients with stable disease or better have progressed with a median follow-up of 10 months (range 6–13 months). Response to therapy is associated with cumulative dose of thalidomide. Patients who responded to therapy received a median thalidomide cumulative dose of 37,600 (range 5700–74,500) mg as compared to 5,650 (range 2100–21,000) mg among non-responding or stable disease patients. These studies demonstrate that thalidomide in combination with rituximab is active in WM, and associated with the cumulative dose of thalidomide. In view of the encouraging response rates obtained with this combination and the potential for improved toxicity profile, a phase II study examining the thalidomide analogue CC-5013 (Revlimid) plus rituximab is planned.

Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7031-7031
Author(s):  
Azra Raza ◽  
Siddhartha Mukherjee ◽  
Andrew Eisenberger ◽  
J. Gregory Mears ◽  
Francois Wilhelm
Keyword(s):  
Side Effects ◽  
Phase Ii ◽  
Lower Risk ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Preliminary Results ◽  
Transfusion Independence ◽  
Molecule Inhibitor ◽  
Study Results

7031 Background: Rigosertib, a novel small molecule inhibitor of PI3-Kinase and PLK pathways is currently evaluated (IV infusions) in a phase III trial in higher risk MDS patients who have failed hypomethylating agents. A previous phase I study found good bioavailability and activity of orally administered rigosertib in transfusion-dependent MDS patients (ASH 2011). Here we report preliminary results from an ongoing phase II study. Methods: This is a randomized, two-arm study of oral rigosertib (560 mg bid) administered either intermittently (2 out of 3 weeks) or continuously. Transfusion-dependent patients must have received at least 4 units RBC transfusions over 8 weeks before randomization, and can receive transfusions and erythrocyte stimulating agents (ESAs) while on study. Results: Twenty nine MDS patients (25 intermediate-1 and 4 low risk per IPSS classification) have been randomized as of December 17, 2012. Overall oral rigosertib was well tolerated except for a high incidence (5 of 9 patients) of grade 2+ urinary side effects (dysuria, hematuria, cystitis, and urinary urgency), in the continuous dosing arm. Accordingly, the protocol was amended to allow all patients to be treated with intermittent dosing, with option of dose interruption/reduction resulting in a much lower frequency of urinary side effects (4/20 patients with urinary grade 2+ toxicity). Fifteen patients (none of them with del5q cytogenetic) have been treated with intermittent dosing for at least 8 weeks. Seven (47%) patients achieved transfusion independence (no RBC transfusion for at least 8 consecutive weeks), which lasted 8 to 27 + weeks. Six of 7 responding patients were refractory to prior treatment with ESAs and 5 of these 7 patients received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance. Conclusions: Preliminary results of this phase II study indicate that intermittent dosing of rigosertib administered orally is well tolerated and active in producing transfusion independence in approximately 50% transfusion dependent, lower risk MDS patients. The contributing role of rigosertib and ESAs in these transfusion responses is being investigated. Clinical trial information: NCT01584531.

scholarly journals Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx®): a placebo-controlled randomised phase II study (PLIANT)

2017 ◽  
Vol 57 (3) ◽  
pp. 393-402 ◽  
Author(s):  
Bengt Glimelius ◽  
Nebojsa Manojlovic ◽  
Per Pfeiffer ◽  
Baadur Mosidze ◽  
Galina Kurteva ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase Ii ◽  
Phase Ii Study

High-dose busulfan and cyclophosphamide with autologous bone marrow transplantation support in advanced malignancies in children: a phase II study.

1986 ◽  
Vol 4 (12) ◽  
pp. 1804-1810 ◽  
Author(s):  
O Hartmann ◽  
E Benhamou ◽  
F Beaujean ◽  
J L Pico ◽  
C Kalifa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Phase Ii ◽  
Marrow Transplantation ◽  
Residual Disease ◽  
Phase Ii Study ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Terminal State ◽  
High Dose

Twenty children with advanced, nonleukemic malignancies entered a phase II study of high-dose busulfan-cyclophosphamide followed by bone marrow transplantation (BMT). All had disease refractory to conventional and/or high-dose chemotherapy (HDC). There were ten neuroblastoma patients, six non-Hodgkin's lymphoma, three Ewing's sarcoma, and one rhabdomyosarcoma. Eight had primarily resistant disease, ten were in second progressive relapse, and two in third progressive relapse. One patient was not evaluable for response. Among the 19 evaluable patients the responses observed were complete response (CR), seven; partial response (PR), three; objective effect, five; and failure, four. However, survival was poor: 15 patients died, two are alive with disease, and three are alive with no evidence of disease (NED) at 8+, 11+, 14+ months post-BMT. Toxicity was high but considered as acceptable, taking into account the terminal state of these patients. Seven treatment-related deaths were observed. This combination therapy proved to be highly effective, with a response rate of 50%, and its value for eradication of residual disease in less advanced patients should be investigated.

Allogeneic blood cell transplantation without posttransplant colony-stimulating factors in patients with hematopoietic neoplasm: a phase II study.

1996 ◽  
Vol 14 (4) ◽  
pp. 1314-1319 ◽  
Author(s):  
C Rosenfeld ◽  
R Collins ◽  
L Piñeiro ◽  
E Agura ◽  
J Nemunaitis
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Blood Cell ◽  
Cell Transplantation ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Chronic Gvhd ◽  
Allogeneic Blood ◽  
Platelet Recovery ◽  
Colony Stimulating Factors

PURPOSE There is limited experience with allogeneic blood cell transplantation (BCT). In an earlier pilot study, the combination of bone marrow and blood did not produce severe acute graft-versus-host disease (GVHD). We now report the results of a phase II study using blood stem cells alone in 19 patients. PATIENTS AND METHODS The median age was 40 years. All patients had hematopoietic malignancies and received transplants from HLA-identical sibling donors. GVHD prophylaxis consisted of cyclosporine plus prednisone. Posttransplant colony-stimulating factors were not administered. Donors were mobilized with subcutaneous granulocyte colony-stimulating factor (G-CSF; 16 microg/kg/d) for 5 days. Apheresis was performed on 2 consecutive days. RESULTS The median cell content of the two apheresis was 11.9 x 10(8) WBC/kg, 3.2 x 10(8) CD3/kg, and 8.3 x 10(6) CD34/kg. The median time to achieve an absolute neutrophil count (ANC) > or = 500/microL was 13 days, and 14 days to a platelet count > or = 50,000/microL. All patients engrafted. Platelet recovery was faster in marrow historic control groups. Blood cells in all tested cases contained more than 95% donor cells on day 30. The actuarial incidence of acute GVHD was 37%, and 13% for grade II-IV GVHD. Limited, corticosteroid responsive, chronic GVHD developed in 33% of assessable patients. At a median follow-up of 192 days, actuarial survival was 75%. CONCLUSION Transplantation of a high number of stem cells may lead to rapid engraftment without the use of posttransplant colony-stimulating factors. GVHD does not appear to be more severe than in similarly treated patients undergoing bone marrow transplantation. For allogeneic transplantation, mobilized blood cell collections are an alternative to bone marrow collections.

Sign in / Sign up

Export Citation Format

Share Document