Enzastaurin in Previously Treated Waldenstrom's Macroglobulinemia: An Open-Label, Multicenter, Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3867-3867
Author(s):  
Irene M Ghobrial ◽  
Jean-Luc Harousseau ◽  
Steven P Treon ◽  
Brianna Harris ◽  
Courtney E Lin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Waldenström’S Macroglobulinemia ◽  
Two Stage ◽  
Advisory Committees ◽  
Minor Response ◽  
Previously Treated ◽  
Grade 3 ◽  
A Minor ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 3867 Poster Board III-803 Background Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM), and clinical studies suggest encouraging activity and a well-tolerated safety profile in a variety of hematologic cancers. We are conducting a multicenter, two (parallel) cohort, two-stage, phase II trial to determine whether further study of single-agent enzastaurin is warranted in patients with previously treated WM or MM. The primary objective is to assess the response rate (RR); secondary objectives include assessment of time to progression (TTP), safety, biomarkers, and the impact of adding dexamethasone to enzastaurin in patients with progressive disease (PD). Preliminary results for the WM cohort are reported here. Methods Eligible patients with WM and 1-5 prior therapies were enrolled and treated with 250 mg oral enzastaurin twice daily (1125-mg loading dose on day 1) in 28-day cycles. Patients continued for 8 cycles or until PD or unacceptable toxicity occurred. At the investigator's discretion, dexamethasone (20-40 mg po QD, days 1-4, 9-12, and 17-20 for 4 cycles; days 1-4 of each cycle thereafter) was added to enzastaurin in patients with PD. According to the Simon two-stage design, if 2 of the first 10 patients (in stage 1) experienced a minor response (MR) or better, then the study would be expanded to 29 patients (stage 2). Best response was determined according to the response assessment recommendations of the Third International Workshop on WM (IWWM). Adverse events were graded according to CTCAE version 3.0. Results Twenty-nine patients (7 females, 22 males) with WM were enrolled. The median age was 65.6 years (range: 51.7-82.3 years) and 93% of patients had an Eastern Cooperative Oncology Group performance status of 0. Patients had a median of 2 prior systemic therapies and 26 patients (89.7%) had prior rituximab. Patients completed a median of 4 cycles. Six patients received ≥6 cycles of enzastaurin treatment. Twenty patients remain on study. There were no drug-related discontinuations. None of the patients had a complete response (CR). One patient had a partial response (PR) and 7 patients had a minor response (MR), for a RR (CR+PR+MR) of 27.6%. Immunoglobulin M decreased by ≥25% in 11 patients. Three (10.3%) patients had a PD. One patient had a drug-related grade 3 wound complication; there were no other drug-related grade ≥3 toxicities. One patient died on study due to infection unrelated to enzastaurin. Conclusions Although the results are preliminary, enzastaurin appears to have activity and is well tolerated in patients with previously treated WM. The WM cohort was expanded to allow up to 50 patients to be treated on study. Disclosures: Ghobrial: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Research Funding, Speakers Bureau. Lin:Eli Lilly and Company: Employment. Yuan:Eli Lilly and Company: Employment. Benhadji:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Leblond:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

Phase II Trial of Weekly Bortezomib in Combination with Rituximab in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2727-2727
Author(s):  
Irene M. Ghobrial ◽  
Fangxin Hong ◽  
Swaminathan Padmanabhan ◽  
Ashraf Z. Badros ◽  
Meghan Rourke ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Significant Activity ◽  
Waldenström’S Macroglobulinemia ◽  
Advisory Committees ◽  
Minor Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Grade 3 ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 2727 Poster Board II-703 INTRODUCTION: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenstrom's Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy were eligible. All patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days x 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response. RESULTS: Thirty-seven patients were treated. Majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI: [65,92]) with 2 patients (5%) in complete remission (CR)/near CR, 17 (46%) in partial response (PR), and 11(30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4–21.1). Death occurred in 1 patient due to viral pneumonia. The most common grade 3 and 4 therapy related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade-3 peripheral neuropathy occurred in only 2 patients (5%). The median event-free survival (EFS) is 12 months (95% CI, 11–20) with estimated 12 month and 18 month EFS of 49% (95% CI: [31, 67%]) and 38% (95% CI: [20, 56%]). The median overall survival has not been reached. CONCLUSIONS: The combination of weekly bortezomib and rituximab showed significant activity and minimal neurological toxicity in patients with relapsed WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees.

Phase II Trial of Weekly Bortezomib in Combination with Rituximab in Untreated Patients with Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3752-3752
Author(s):  
Irene M. Ghobrial ◽  
Swaminathan Padmanabhan ◽  
Ashraf Z. Badros ◽  
Renee Leduc ◽  
Meghan Rourke ◽  
...  
Keyword(s):  
Herpes Zoster ◽  
Board Of Directors ◽  
Research Funding ◽  
Waldenström’S Macroglobulinemia ◽  
Advisory Committees ◽  
Minor Response ◽  
Waldenstrom's Macroglobulinemia ◽  
A Minor ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 3752 Poster Board III-688 INTRODUCTION This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenstrom's Macroglobulinemia (WM). Prior studies using twice a week bortezomib in this population showed high responses, but significant neuropathy. METHODS Patients who had symptomatic WM and were not previously treated were eligible. All patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days x 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Dexamethasone was not added. Primary endpoint was the percent of patients with at least a minor response. Patients were encouraged to receive herpes zoster prophylaxis but it was not mandated. RESULTS Twenty-six patients were treated. At least minimal response or better was observed, assessed using serum protein electropheresis, in 24/26 cases (92%) with 2 patients (8%) in complete remission (CR)/near CR, 15 (54%) in partial response (PR), and 7(27%) in minimal response (MR). Two patients (8%) had stable disease. By using IgM by nephlometry, all 26 patients (100%) had at least a minor response, with 2 (8%) CR, 15 (58%) in PR and 9 (35%) with minor response. The median time of follow up is 11.2 months (range, 3-18.6). To date, six (23%) patients have developed progressive disease or required a new therapy. A single patient has died due to disease progression. The median progression-free survival and overall survival have not been reached. The most common grade 3 and 4 therapy related adverse events included anemia in 3 patients, lymphopenia in 2 patients; neutropenia, leucopenia, thrombocytopenia, pneumonia, fatigue, allergic reaction and nausea and vomiting in 1 patient for each. Five patients developed grade 2 peripheral neuropathy including 4 did who did not have neuropathy at baseline. It required dose reductions in cycles 4 and 5 and these neuropathies resolved to grade 1 or less with follow up. One case developed grade 1 herpes zoster reactivation in cycle 1. CONCLUSIONS The combination of weekly bortezomib and rituximab showed significant activity and minimal neurological toxicity in patients with untreated WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson:Keryx Biopharmaceuticals: Honoraria. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees.

Long-lasting responses after four doses of rituximab in Waldenström's macroglobulinemia: Clinical value of minor responses: A follow-up of the Eastern Cooperative Oncology Group E3A98 trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8513-8513
Author(s):  
M. A. Gertz ◽  
R. Abonour ◽  
L. T. Heffner ◽  
P. R. Greipp ◽  
H. Uno ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Waldenström’S Macroglobulinemia ◽  
Minor Response ◽  
Free Survival ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
A Minor ◽  
Waldenström's Macroglobulinemia

8513 Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival. No significant financial relationships to disclose.

scholarly journals Updated Results from a Phase II Study of the Fc Engineered CD19 Antibody MOR208 in Combination with Lenalidomide for Patients with Chronic Lymphocytic Leukemia (CLL) and Richter's Transformation or Ibrutinib for Patients with Ibrutinib-Resistant Clones

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4386-4386 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Amy S. Ruppert ◽  
Farrukh T. Awan ◽  
Jeffrey Jones ◽  
Leslie A. Andritsos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Variant Allele Frequency ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract MOR208 is an Fc engineered CD19 monoclonal antibody with preliminary efficacy in CLL as a single agent (Woyach et al, Blood 2014). Compared to non-engineered antibodies, MOR208 has significantly enhanced antibody dependent cellular cytotoxicity (ADCC), which can be further augmented in vitro with the addition of lenalidomide. Given the potential synergy of these agents, acceptable individual safety profiles, and efficacy of each as a single agent, we chose to combine MOR208 and lenalidomide in patients (pts) with previously treated and previously untreated CLL and in pts who have undergone Richter's Transformation (RT). Because recent data show poor outcomes in pts who relapse after the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib and the presence of mutations in BTK prior to relapse, we included a cohort of ibrutinib-treated pts with identified resistance mutations but no clinical relapse where MOR208 was added to ibrutinib. This study is a single institution phase II trial of MOR208 in combination with lenalidomide or MOR208 in combination with ibrutinib with an initial safety run-in as part of each cohort. In combination with lenalidomide, MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, 9 mg/kg on days 2, 8, 15, and 22 of cycle 1, and day 1 of cycles 2-12. Lenalidomide was started at a dose of 2.5 mg daily on cycle 1 day 8 and given continuously. The dose of lenalidomide could be escalated up to 10 mg daily in pts without toxicity. After 12 cycles, lenalidomide could be continued indefinitely in responding pts. In combination with ibrutinib, ibrutinib was continued at a dose of 420 mg daily, and MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, 12 mg/kg on days 2, 8, 15, and 22 of cycle 1, then weekly during cycles 2 and 3, and every other week through cycle 12. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events (AE) v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. For pts on MOR208 plus ibrutinib, variant allele frequency of mutant BTK was measured every 3 cycles. In the previously untreated cohort, 11 pts have been enrolled, with a median age of 62 (range 44-75). 1 pt had both del(17p) and del(11q) on FISH. Grade 3/4 adverse events regardless of attribution have been uncommon and have included hypertension (3 pts), infusion reaction (2 pts), and fatigue, neutropenia, colitis, hyperglycemia, dyspnea, and sinusitis (1 pt each). After a protocol amendment augmenting steroid premedication, no further grade 3 infusion reactions were observed. In the previously treated cohort, 11 pts have been enrolled, with a median age of 70 (range 62-75). 2 pts each had del(17p) and del(11q) on FISH, and 8 have Zap-70 methylated disease. Grade 3/4 toxicities regardless of attribution have included neutropenia (6), hyperglycemia (2), hypertension (2), and thrombocytopenia, fatigue, anemia, upper respiratory infection, catheter related infection, hypercalcemia, hypophosphatemia, infection, respiratory failure, and sepsis in 1 pt each. In the RT cohort, 5 pts have been enrolled, with a median age of 60 (range 55-70). Four had previously treated CLL, and one was previously untreated. Three had del(17p) and 2 had del(11q) on FISH. Grade 3/4 toxicities included hyperglycemia (3) and hyponatremia, thrombocytopenia, and neutropenia in 1 pt each. In the cohort of pts with molecular progression on ibrutinib, 7 pts have been enrolled, with a median age of 62 (range 45-77). Five have del(17p), 1 of whom also has del(11q). Grade 3/4 toxicities have included hypertension (2) and hyperglycemia and hyperuricemia in 1 pt each. Four pts have been on study for at least 3 cycles. One pt had an increase in BTK C481S variant allele frequency (VAF) from 66.3% to 78.8% while the others all have decreased (15.1% to 3.7%, 46.4% to 34.9%, and 67.2% to 18.1%). No pt has developed progressive disease. In conclusion, this Phase II trial in progress demonstrates preliminary safety and activity of the combination of MOR208 and lenalidomide in pts with CLL. This combination also has the potential to positively modulate the immune system, and detailed correlative studies will evaluate T- and NK-cell function. MOR208 appears safe in combination with ibrutinib, and preliminary evidence of activity against CLL cells with BTK C481S has been observed. Trial accrual is ongoing and updated results will be presented at the meeting. Disclosures Woyach: Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Lozanski:Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Phase II Pilot Study of Rituximab + CHOP in Patients with Newly Diagnosed Waldenström’s Macroglobulinemia, an Eastren Cooperative Oncology Group Trial (Study E1A02).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3616-3616 ◽  
Author(s):  
Rafat Abonour ◽  
Lijun A. Zhang ◽  
Vincent Rajkumar ◽  
Gordan Srkalovic ◽  
Philip R. Greipp ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Response Rate ◽  
Objective Response ◽  
Visual Disturbance ◽  
Low Grade ◽  
Minor Response ◽  
Duration Of Response ◽  
Grade 3 ◽  
A Minor

Abstract Waldenström’s Macroglobulinemia (WM) is a low-grade lymphoplasmacytic disorder associated with an IgM monoclonal protein that may present with anemia, lymphadenopathy, and hepatosplenomegaly. Since combination chemotherapy and Rituximab are both active in this disease, it is possible the response rate can be enhanced by using a combined modality of Rituximab and CHOP. This approach has been used in indolent lymphoma with remarkable results and limited toxicity. Objective: To determine the response rate in previously untreated patients with Waldenström’s Macroglobulinemia receiving rituximab and CHOP. Methods: This was a phase II study of standard R-CHOP in symptomatic WM patients. The study was activated on June 15, 2004 and closed on April 26, 2007 due to poor accrual. The median age of the sixteen patients enrolled was 60 (44–79 years), β2M 3 ug/ml (2.1–7.6), median hemoglobulin was 9 g/dl (7.7–10.9), Viscosity 3.4(1.6–10), and IgM 6389 (3229–13300 mg/dl). The most common symptoms were Fatigue (13/16), visual disturbance (7/16) and parasthesias or painful/numb feet (6/16). Only one patient had bulky adenopathy (6.3%). Results: Of 16 patients treated, 5 patients have no response data available (it will be presented at the meeting). Objective response was 91% (90% CI: 63.5% ∼ 99.5%) and 1 patient had a minor response with an overall response rate of 100%. Median time to response was 1.6 months from registration and median time to maximum response was 2.1 months. Median duration of response has not been reached. The median follow up time of the 16 patients was 18.3 months with a range of 3.6–24.8 months. Among the 16 treated patients, there were 8 (50%, 90% exact binomial CI: 27.9%∼72.1%) grade 4 neutropenia. 8 patients experienced grade 3 lymphopenia (50%, 90% exact binomial CI: 27.9%∼72.1%). Only 2 grade 3 febrile neutropenia were noted. As of August 4, 2007, none of the 16 patients has died. R-CHOP is a promising regimen in the treatment of patients with Waldenström’s Macroglobulinemia. To succeed in completing clinical trials in this rare disease better international collaboration and involvement in advocacy groups are required.

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab (CMA) Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Advanced Hematologic Malignancies: Determination of MTD and Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 197-197 ◽  
Author(s):  
Koen van Besien ◽  
Justin Kline ◽  
Lucy A Godley ◽  
Richard A. Larson ◽  
Vu H. Nguyen ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Phase Ii ◽  
Renal Toxicity ◽  
Phase Ii Study ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Grade 3 ◽  
One Year

Abstract Abstract 197 Supported by an unrestricted grant from Genzyme Corporation. Fludarabine (Flu) melphalan-alemtuzumab is a well tolerated, reduced intensity conditioning regimen for HCT. Clofarabine (Clo), a second generation nucleoside analog with excellent activity in acute leukemia, might enhance disease control over Flu. We report outcomes of a completed phase I and ongoing phase II study of CMA conditioning for allogeneic peripheral blood HCT. Tacrolimus was administered as GVHD prophylaxis. For the phase I cohort, one pt was enrolled per dose level, until the first DLT or until 2 had grade 3 toxicity. Dose level 1 consisted of: clo 10 mg/m2/day on d −7 to −3 and melphalan 100 mg/m2 on day −2. Clo was increased by 10 mg/m2/day per cohort until 40 mg/m2/day. Then, melphalan was increased by 20 mg/m2 until 140 mg/m2. Alemtuzumab was given at a fixed dose of 20 mg/day on d −7 to −3. Twelve pts were accrued in the phase I portion of whom three remain in remission at 26, 22 and 21 months. Forty pts, median age 53 (24–69), have been accrued in the phase II study of whom 16 had related and 24 unrelated donors. 20 had AML/MDS (6 refractory, 4 CR2, 9 CR1, 1 untreated MDS), 16 NHL (6 refractory, 9 chemosensitive relapse, 1 CR1) 2 CLL, 2 MPD. ASBMT risk score was high in 14, intermediate in 14, and low in 12. Performance score was 0 in 19, 1 in 17, 2 in 2, and not documented in 2 patients. The phase II dose was initiated at Clo 40 mg/m2/day x 5 days and melphalan 140 mg/m2. Twenty-four pts received this dose. Grade 3 renal toxicity occurred between day −7 and day +7 in 4 of 24 (17%) pts receiving this dose. The phase II dose was then reduced to Clo 30 mg/m2/day x 5 days and melphalan 140 mg/m2, and used to treat 16 pts. One pt with preexisting cardiomyopathy and refractory AML died during conditioning from cardiovascular failure. No grade 3 renal toxicity has been observed in this cohort and 3 pts had reversible grade 2 renal failure. Other toxicities included: gr 2–3 reversible ALT elevation between day −2 and day +5 in 8 pts; gr 2 reversible bilirubin elevation in 1 pt. No grade 3–4 hand foot syndrome or VOD occurred in this cohort. All evaluable pts engrafted. Twenty of 24 pts had full donor CD3 chimerism on day 30 and 2 had mixed donor chimerism. 11 pts had gr II aGVHD, and 3 had gr IIII/IV aGVHD. 7 have cGVHD.With a median follow-up of 313 days (19–607), 24 of 40 pts (60%) in the phase II portion of the study remain in remission. Eight have relapsed, 4 of whom have died. Eight others have died of treatment-related causes (7 after Clo 40 and 1 after Clo 30). Estimated one year survival is 72% (95%CI, 56–88) and PFS is 63% (45–81%). Neither dose of Clo (40 vs 30), donor type (MUD vs related), age (< 50 vs >50) affected outcomes. One year PFS was 56% (28–84) for NHL and 68% (46–90) for AML/MDS (P=NS). One year PFS was 43% (15–71%) for ASBMT high risk pts vs 70% (50–90%) for ASBMT low/intermediate risk pts (P=0.01; Figure 1). Conclusions: Clofarabine - melphalan - alemtuzumab conditioning induces durable remissions in a substantial fraction of patients with advanced hematologic malignancies. Clo 30/Mel 140 has an excellent safety profile. Disclosures: Off Label Use: clofarabine for transplant conditioning. Kline:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Odenike:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Stock:Genzyme: Research Funding.

A Phase II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Relapsed or Refractory Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 587-587
Author(s):  
Irene M Ghobrial ◽  
Morie A Gertz ◽  
Betsy LaPlant ◽  
John Camoriano ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Waldenström’S Macroglobulinemia ◽  
Advisory Committees ◽  
Overall Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 587 Background: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenstrom's macroglobulinemia (WM). Patients and Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 × 106/L, a neutrophil count ≥1,000 × 106/L, and a creatinine and bilirubin ≤2x laboratory upper limit of normal. Patients received everolimus 10 mg PO daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 50 pts were treated. The median age was 63 years (range, 43-85). The overall response rate (CR+PR+MR) was 70% (95% CI: 55-82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) has not been reached. The estimated PFS at 6 and 12 months is 75% (95%CI: 64-89%) and 62% (95%CI: 48-80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient group. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Witzig:Novartis: Research Funding.

Primary Therapy of Waldenström's Macroglobulinemia (WM) with Weekly Bortezomib, Low-Dose Dexamethasone and Rituximab (BDR): A Phase II Study of the European Myeloma Network

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1941-1941 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Ramón García-Sanz ◽  
Maria Gavriatopoulou ◽  
Pierre Morel ◽  
Marie-Christine Kyrtsonis ◽  
...  
Keyword(s):  
Herpes Zoster ◽  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Standard Dose ◽  
Single Agent ◽  
Primary Therapy ◽  
Advisory Committees ◽  
Ortho Biotech ◽  
Grade 3

Abstract Abstract 1941 Rituximab and bortezomib are active agents in the treatment of WM. Based on preclinical studies which indicated synergism between bortezomib and rituximab, in 2006 we designed a large phase II multicenter trial to evaluate the combination of these agents in previously untreated patients with WM requiring therapy based on consensus recommendations (Kyle et al, Sem Oncol 2003;30:116). This trial was conducted by the European Myeloma Network in 10 centers. In order to prevent the “IgM flare effect” seen with rituximab-based regimens, one course of single agent bortezomib was first administered at a standard dose of 1.3 mg/m2 IV on days 1, 4, 8 and 11. Ten days later, the patients received four courses of 35 days duration each. In courses 2 to 5, bortezomib was administered weekly at a dose of 1.6 mg/m2 on days 1, 8, 15 and 22. During courses 2 and 5, immediately after the administration of bortezomib, patients received dexamethasone 40 mg IV followed by rituximab 375 mg/m2 IV. Patients received a total of 8 infusions of rituximab. Bortezomib was administered weekly in order to reduce the incidence of neurotoxicity which can be significant in WM patients treated with standard schedule bortezomib (Treon et al, Clin Cancer Res 2007;13:3320). A single dose of dexamethasone was given before each dose or rituximab in order to take advantage of potential synergism with rituximab and to reduce allergic reactions but to avoid steroid-induced complications. During treatment, valacyclovir prophylaxis for herpes zoster was prescribed. After completion of treatment, patients with CR, PR, MR or SD according to consensus criteria (Kimby et al, CLM 2006;3:380) were followed without further therapy until there was evidence of progressive disease. Dose modifications for toxicity were allowed and bortezomib could be reduced from 1.6 mg/m2 to 1.3 mg/m2 to 1.0 mg/m2. The trial was initiated in March 2007, 61 patients were scheduled to be enrolled and the study completed accrual in June 2010. Patients characteristics included: age >65 years in 60% of patients, hemoglobin <11.5 g/dL in 82%, platelet count <100×109/L in 17%, β2-microglobulin >3 mg/dL in 63%, serum monoclonal protein >7 g/dL in 3.4%, lymphadenopathy in 42%, splenomegaly in 29%, and B-symptoms in 42% of patients. According to IPSS for WM, 18% of patients were rated as low risk, 23% as intermediate risk and 59% as high risk. The main reasons to start treatment included cytopenias in 43% of patients, hyperviscosity in 22%, presence of B-symptoms in 18% and lymphadenopathy in 8%. So far, 54 patients are evaluable for response. On an intent to treat, response rating include CR in 2 (4%), PR in 33 (61%), MR in 8 (15%), SD in 5 (9%) and PD in 6 (11%) patients. In responding patients, at least MR occurred within 2.3 months of treatment and the median time to best response is 4.8 months. Plasmapheresis was not required in any patient before or after treatment with BDR. An “IgM flare phenomenon” was not seen and this was attributed to the initial course of single agent bortezomib. Median follow up for all patients is 12 months, and so far 10 patients have progressed. Eight patients have died, 5 due to causes unrelated to WM or complications of treatment. Toxicities include: neutropenia (grade ≥3) in 13% of patients; thrombocytopenia (grade ≥3) in 5%; peripheral sensory neuropathy, grade 1,2 in 30%, but grade ≥3 in only 5%; neuropathic pain in 17%, but grade ≥3 in only 2%, gastrointestinal toxicity, grade 3 in 7%; and infections in 17% (grade ≥3 in 7%). One patient died of septic shock in absence of neutropenia. Three patients (5%) experienced pulmonary toxicity (grade 3/4) which was attributed to bortezomib and consisted of dyspnea, decrease of O2 saturation and diffuse pulmonary infiltrates on chest CT scan. This toxicity resolved completely after administration of steroids and 2 of 3 patients continued treatment as per protocol. Only one patient (who had discontinued valacylovir prophylaxis) developed herpes zoster. The dose of bortezomib was reduced in 30% of patients primarily because of peripheral neuropathy. This is the largest trial that has evaluated the role of a bortezomib-containing regimen in the frontline setting of symptomatic patients with WM, most of whom were rated as high risk according to IPSS. We conclude that the BDR regimen is active. An update on response, toxicity and time to progression will be performed in November 2010. Disclosures: Dimopoulos: Ortho-Biotech: Honoraria; Millennium: Honoraria. Off Label Use: Bortezomib for Waldenstrom's Macroglobulinemia. García-Sanz:Ortho-Biotech: Honoraria; Millennium: Honoraria; Celgene: Honoraria. Merlini:Millennium: Honoraria; Ortho-Biotech: Honoraria. Sonneveld:Ortho-Biotech: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Phase II Trial of Rituximab in the Treatment of Inhibitors in Congenital Hemophilia A: Results of the RICH Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 27-27 ◽  
Author(s):  
Cindy A. Leissinger ◽  
Rebecca Kruse-Jarres ◽  
Suzanne Granger ◽  
Barbara A Konkle ◽  
Margaret V. Ragni ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Null Hypothesis ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Minor Response ◽  
Inhibitor Titer

Abstract Abstract 27 Antibodies (inhibitors) to exogenously administered factor VIII (FVIII) develop in as many as 30 – 40% of patients with severe hemophilia A. Patients with persistent inhibitors are at increased risk of serious, poorly controlled bleeding which results in significant morbidity and in some cases early death. Rituximab, a chimeric murine/human monoclonal antibody directed against CD20, suppresses circulating and tissue B cells and pre-B cells and has been used in the treatment of a variety of autoimmune and alloimmune disorders. The primary objective of this NHLBI Transfusion Medicine Hemostasis network-sponsored study was to evaluate the role of rituximab as an approach to inhibit the production of FVIII antibodies in patients with severe congenital hemophilia A and high titer inhibitors. Methods: This was a prospective, multi-institution, single-arm, open-label Phase II trial. Eligible subjects were males over 18 months of age with severe hemophilia A and a history of an inhibitor ≥5 Bethesda units (BU). Individuals who were HIV positive, undergoing immune tolerance, or receiving immune modulating therapies were excluded. Following a challenge dose of recombinant FVIII (rAHF-PFM) at 50 IU/kg, and evidence of an inhibitor titer ≥ 5 BU at 5 – 14 days after the challenge dose, subjects received rituximab 375 mg/m2 weekly for 4 weeks. Starting two weeks after the fourth rituximab treatment, inhibitor titers were drawn every 4 weeks. A major response was defined as a fall in the inhibitor titer to < 5 BU at any time up to and including week 22, with the titer remaining < 5 BU following re-challenge with FVIII. A minor response was defined as inhibitor falling to < 5 BU at any time up to and including week 22, with the anamnestic peak following re-challenge with FVIII between 5–10 BU and less than 50% of the original anamnestic peak. The null hypothesis was that no more than 5% of subjects treated with rituximab would be major responders. Results: A total of 23 subjects were enrolled; 21 received the initial FVIII challenge. Of these, 4 subjects did not meet the criteria to receive rituximab treatment, and 1 subject withdrew consent. A total of 16 subjects received at least one dose of rituximab and are included in this analysis. The median age was 14 y (range 4 – 38 y). Three subjects (18.8%) had a major response. If the null hypothesis were true, the probability of 3 or more major responses in 16 subjects would be 0.043, so the null hypothesis was rejected. One subject (6.2%) had a minor response to treatment. All 4 responders and 8 non-responders had a baseline inhibitor titer < 20 BU, resulting in a response rate of 33% in that group vs. 0% in the 4 subjects with a baseline inhibitor titer ≥ 20 BU. Discussion: Infusion of rituximab 375 mg/m2 once per week for four weeks was effective in reducing the anamnestic inhibitor response in 25% of severe hemophilia A subjects with inhibitors who were not receiving concurrent immune tolerance therapy. Those who responded tended to have lower baseline inhibitor levels compared to the group that did not meet the criteria for response. This Phase II study, designed as a proof of concept, demonstrated that rituximab may be useful in lowering inhibitor levels and anamnesis in some patients with inhibitors, but that the effect as a solo treatment strategy is modest, and possibly restricted to patients with inhibitor titers under 20 BU. Further studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerization strategies. Acknowledgments: The authors acknowledge the support of Genentech for the provision of rituximab and partial financial support for the study. The authors also acknowledge Baxter Healthcare Corporation for donating the recombinant FVIII used in the trial. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab, a drug approved for use in treating lymphoma, was studied for its efficacy in suppressing inhibitors against factor VIII in patients with hemophilia and high titer inhibitors. Kruse-Jarres:Baxter: Consultancy, Honoraria; Bayer:; Griforls: Consultancy, Honoraria; Inspiration: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria. Konkle:Baxter Corporation: Consultancy, Research Funding; Bayer Corp: Consultancy; Inspiration Biopharmaceuticals: Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees. Neufeld:Genentech: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Bennett:Biogen IDEC: Honoraria. Valentino:Baxter Bioscience, Bayer Healthcare, GTC Biotherapeutics, NovoNordisk, Pfizer, CSL Behring, Inspiration Bioscience, and Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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