Phase 3 Trial of Pixantrone Dimaleate Compared with Other Agents as Third-Line, Single-Agent Treatment of Relapsed Aggressive Non-Hodgkin Lymphoma (EXTEND): End of Study Results.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2833-2833 ◽  
Author(s):  
Ruth Pettengell ◽  
Pier Luigi Zinzani ◽  
Geetha Narayanan ◽  
Fernando Hurtado de Mendoza ◽  
Raghunadharao Digumarti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Single Agent ◽  
Clinical Activity ◽  
Positive Trend ◽  
Phase 3 ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Study Results ◽  
Grade 3

Abstract Abstract 2833 Introduction: No therapy with reliable, durable efficacy exists for patients with aggressive non-Hodgkin lymphoma (aNHL) who relapse following at least two lines of therapy. Pixantrone dimaleate (PIX) is a novel aza-anthracenedione, structurally similar to anthracyclines and mitoxantrone, and forms stable DNA adducts. Unlike anthracyclines and mitoxantrone, PIX does not bind iron, minimally promotes reactive oxygen species formation, and is substantially less cardiotoxic in preclinical models. On the basis of promising early clinical activity and acceptable safety, we conducted a phase 3 trial with PIX in patients with aNHL and ≥2 relapses. Patients and Methods: This randomized, multicenter, controlled, open-label study enrolled patients with aNHL (de novo or transformed) with ≥1 prior anthracycline-containing regimen and ≥2 relapses. Patients were randomized to PIX 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle, for up to 6 cycles, or to investigator's choice of single-agent comparator (COMP): vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, or, in the US only, gemcitabine or rituximab. Both groups were followed for 18 months after last treatment. The primary endpoint, CR/CRu rate in ITT population, was assessed by an independent assessment panel. Other efficacy endpoints were overall response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Final end-of-study results are reported here. Results: Planned enrollment was set at 320 patients; however, due to slow accrual, a total of 140 patients were randomized (n=70 per group) to this study. Median number of treatment cycles for PIX group was 4 vs 3 for COMP. Median duration of treatment for patients in the PIX group was about one month longer than in the COMP group (3.8 vs 2.6 months). The end-of-study CR/CRu rate was 24% (16% CR, 8%CRu) for PIX vs 7% (no CRs, 7% CRu only) for COMP (P = 0.009); ORR (CR/CRu/PR) was 40% vs 14% (P = 0.001). After treatment ended, 3 patients in the PIX group achieved CR with no subsequent therapy. Two of the 3 patients converted from SD to CR and 1 from PR to CRu. Median CR/CRu duration was 9.6 months for PIX vs 4.0 months for COMP (P = 0.081). For survival endpoints, there was a 40% improvement in PFS with a median of 5.3 months vs 2.6 months (HR = 0.60, log-rank P = 0.005) and a 21% improvement in OS with a median of 10.2 months for PIX vs 7.6 months for COMP (HR = 0.79, log-rank P = 0.251). Exploratory subgroup analyses of CR/CRu and ORR were consistently higher for PIX patients and suggest stronger efficacy with the subgroups sex (female), <3 prior regimens, no prior rituximab, and ≥1 yr from 1st to 2nd line therapy. During treatment, neutropenia and leukopenia were the most common (≥10%) grade 3/4 adverse events and the incidence of febrile neutropenia was 7.4% for PIX vs 3% for COMP. Percentage of patients with cardiac disorder SAEs was 8.8% for PIX vs 4.5% for COMP. There were 11 grade 1/2 and 2 grade 3 LVEF events for PIX vs 7 grade 1/2 for COMP. Conclusions: In this phase 3 study, patients treated with PIX achieved superior efficacy when compared with other agents, as assessed by CR/CRu rate, ORR, and PFS, and had a positive trend in OS. Pixantrone had a tolerable safety profile in heavily pretreated patients with relapsed aggressive NHL. Disclosures: Pettengell: Cell Therapeutics, Inc: Honoraria. Coiffier:Cell Therapeutics, Inc: Advisory Board. Schiller:Sunesis: Consultancy; Celgene, Genzyme, Millenium, CTI, Antisoma, Novartis: Research Funding. Rizzieri:Cell Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees. Cernohous:Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment, Membership on an entity's Board of Directors or advisory committees; DiaKine Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Dynamo: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1218-1218 ◽  
Author(s):  
Ian W. Flinn ◽  
Carole B. Miller ◽  
Kirit M Ardeshna ◽  
Scott Tetreault ◽  
Sarit E. Assouline ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Clinical Activity ◽  
Phase 2 ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3

Abstract DYNAMO: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma Introduction: Indolent non-Hodgkin lymphoma (iNHL) is characterized by a relapsing clinical course with shorter responses to therapy after each relapse. Duvelisib is an oral dual inhibitor of PI3K-d,γ in development for the treatment of hematologic malignancies, including previously-treated iNHL. Data from a Phase 1 study of duvelisib indicate the potential for duvelisib to be an effective treatment for previously-treated iNHL, with an acceptable safety profile. DYNAMO is a Phase 2 study designed to evaluate the safety and efficacy of duvelisib in a previously-treated, refractory iNHL population. Methods: DYNAMO is an ongoing, open-label, single-arm, safety and efficacy study that includes adult patients (pts) diagnosed with follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or marginal zone lymphoma (MZL) whose disease is refractory to rituximab and to a chemotherapy regimen (containing an alkylator or purine analogue) or radioimmunotherapy. Pts received duvelisib 25 mg twice daily (BID) in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study is overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), time to response (TTR), adverse events (AEs), and changes in safety laboratory values. Pneumocystis jirovecii pneumonia (PJP) prophylaxis was mandated for all patients. Here we present the results from the final analysis, with a data cut-off of 07 April 2016. Results: 129 iNHL pts received at least 1 dose of duvelisib, including 83 pts with FL, 28 with SLL, and 18 with MZL. The median duration of exposure was 6 months (range 0.4 - 23.8). The median age was 65 years, and 68% were male. The median time from initial diagnosis to the first dose of duvelisib was 4.5 years, and from last anticancer therapy was 3.5 months. Pts had received a median of 3 prior regimens (range 1 - 18), with 40% having received ≥ 4 regimens. 77% of patients had disease refractory to ≥ 2 regimens and 96% were refractory to their most recent regimen. 64% of patients previously received bendamustine, 80% of whom were refractory. The ORR was 46% (all PRs, 95% CI 37 - 55), with a median DoR of 9.9 months (95% CI 4.5 - 10.3). The median TTR was 1.9 months (range 1.4 - 11.7). With a median follow-up of 11.5 months, the median PFS was 8.4 months (95% CI 5.8 - 11.3) with a 60% estimated probability of being alive and event-free at 6 months, and the median OS was 18.4 months (95% CI 15.7 - NE) with an estimated probability of survival of 74% at 12 months. 83% of pts experienced a reduction in tumor burden following treatment with duvelisib. The response rate across the disease subtypes was: 41% FL, 68% SLL, and 33% MZL (see Table). AEs were predominantly Grade 1-2. The most common ≥ Grade 3 AEs were transient cytopenias (neutropenia [28%], anemia [12%], and thrombocytopenia [13%]), and diarrhea (15%). 63% of pts had dose modifications (interruptions or reductions) due to AEs and 17% of pts discontinued due to an AE. AEs leading to duvelisib discontinuation in ≥ 2 pts included pneumonitis (n = 3), pneumonia (n = 2), and rash generalized (n = 2). Six pts had an AE with an outcome of death, four assessed as related to duvelisib (suspected viral infection, septic shock, and 2 severe cutaneous reactions [TEN and DRESS]). The incidence of ≥ Grade 3 infection was 20%. The incidence of pneumocystis was 0.8% (1 patient) and the incidence of CMV was 2.3% (3 subjects), none of which were fatal. Conclusions: In the Phase 2 DYNAMO study, duvelisib achieved meaningful clinical activity in a heavily pretreated and highly refractory iNHL population. The safety profile was acceptable, with the majority of AEs low grade (≤ Grade 2) and the majority of pts able to remain on duvelisib. These results suggest duvelisib has a favorable benefit-risk profile in this patient population and further development is ongoing. Table 1 Table 1. Disclosures Flinn: Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Miller:Infinity: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Assouline:BMS: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani:Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Pettitt:Roche: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Infinity: Research Funding. Tournilhac:Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Honoraria, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Honoraria, Research Funding. Crump:Roche: Consultancy; Seattle Genetics: Consultancy; Janssen-Ortho: Consultancy; Celgene: Consultancy. Santabarbara:Infinity: Consultancy. Shi:Infinity: Employment. Steelman:Infinity: Employment. Wagner-Johnston:Pharmacyclics: Speakers Bureau.

Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1528-1528 ◽  
Author(s):  
Wojciech Jurczak ◽  
Pier Luigi Zinzani ◽  
Gianluca Gaidano ◽  
Andre Goy ◽  
Mariano Provencio ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hodgkin's Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Cd20 Antibody ◽  
Grade 3

Abstract Introduction: There remains a high unmet medical need for new therapies for patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is a B-lymphocyte, lineage-specific surface antigen that is highly expressed by most B-cell NHLs. CD19 expression is maintained on lymphoma cells which have CD20 expression downregulated following treatment with the CD20 antibody, rituximab. Consequently, MOR208 (XmAb5574; MOR00208), an Fc-engineered, humanized, monoclonal antibody that targets CD19, may have clinical utility as a new therapeutic approach to R-R NHL. A phase I study showed MOR208 to be safe and well-tolerated with encouraging single-agent activity in patients with chronic lymphocytic leukemia (CLL); an intravenous dose of 12 mg/kg was recommended for phase II studies. Methods: This is a non-randomized, open-label, multicenter, two-stage, phase IIa study of MOR208 in adult patients with R-R NHL whose disease had progressed after at least one prior therapy containing the CD20 antibody, rituximab. In stage 1, 10 patients were to be enrolled into each of four NHL subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent NHL (iNHL) and mantle cell lymphoma (MCL). Patients were to receive single-agent MOR208, 12 mg/kg intravenously, weekly, for 8 weeks (2 cycles). Those with at least stable disease by the 2007 International Response Criteria could continue MOR208 treatment for an additional 4 weeks (total of 12 weeks of therapy). Patients with a complete or partial response (CR or PR) after 12 weeks could then receive MOR208 as maintenance therapy, every 2 or 4 weeks depending on the investigator's decision, until progression. In stage 2, cohorts with ≥2 responses (CR or PR) were to be expanded by at least 20 additional patients. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included duration of response, safety, immunogenicity of MOR208, pharmacokinetics and pharmacodynamics. Results: The DLBCL and FL cohorts were expanded (to N=35 and N=34 patients, respectively), leading to a total enrollment of 92 patients: 56 (61%) were male; median age was 66.5 (range 35-90) years; 80 (87%) had stage III-IV disease; 41 (45%) had received ≥3 prior lines of therapy and 10 (11%) had received a prior stem-cell transplant. The investigator-assessed ORR across all NHL subtypes was 23% (21/92 patients; 16 not evaluable at cutoff) with clinical activity seen in the DLBCL (26% [9/35]; 2 CR, 7 PR); FL (26% [9/34]; 3 CR, 6 PR) and iNHL (27% [3/11]; 2 CR, 1 PR) cohorts (MCL, 0/12 responses). The iNHL cohort was not expanded as the response pattern in this subgroup was heterogeneous according to lymphoma subtype. The longest durations of response recorded to date are 15.4 months for FL and 14.2 months for DLBCL (both ongoing). Grade ≥3 non-hematologic and hematologic treatment-emergent adverse events (TEAEs) were recorded in 24 (26%) and 14 (15%) of 92 patients, respectively. The most commonly reported grade ≥3 hematologic TEAEs were neutropenia (7 [8%] of 92 patients, anemia (4 [4%]), and thrombocytopenia (4 [4%]); such TEAEs were seen most frequently in the DLBCL cohort (10 [29%] of 35 patients overall; neutropenia, 5 [14%], anemia, 4 [11%], thrombocytopenia, 2 [6%]). Dyspnea was the most commonly reported grade ≥3 non-hematologic TEAE (4 [4%] of 92 patients). Infusion-related reactions were seen in 9 (10%) of 92 patients; all were grade 1-2, except for one case of dyspnea, grade 4. There were no treatment-related deaths. Clinical activity in patients with R-R DLBCL appeared to be dependent on attaining a defined cumulative exposure (AUC0-t) over 8 weeks of around 11,000 day*µg/mL; i.e., at the data cutoff date, all 8 patients with a PR after 2 cycles showed an exposure above this potential threshold level. Conclusions: MOR208 demonstrated encouraging single-agent activity with CRs observed in patients with R-R DLBCL, FL, and iNHL. MOR208 was well tolerated without significant infusional toxicity. These data support further development of MOR208 in combination with other agents (including lenalidomide and bendamustine), and protocols for studies in patients with R-R DLBCL are now being developed. Disclosures Jurczak: CELLTRION, Inc,: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano:Celgene: Research Funding; MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy. Korolkiewicz:MorphoSys AG: Employment. Striebel:MorphoSys AG: Employment. Blum:Morphosys: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding.

Bortezomib May Be Safely Combined with Y-90 Ibritumomab Tiuxetan In Patients with Relapsed/Refractory Follicular or Transformed Non-Hodgkin Lymphoma: A Phase I Trial of Combined Induction Therapy and Bortezomib Consolidation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1749-1749
Author(s):  
Rupali Roy ◽  
Andrew M Evens ◽  
David P. Patton ◽  
Annette Larsen ◽  
Alfred Rademaker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Induction Therapy ◽  
Research Funding ◽  
Phase I Trial ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 1749 Background: Preclinical studies suggest that bortezomib, through inhibition of NF-kB activation, may act as a radiosensitizer and enhance the effects of radioimmunotherapy. Methods: This phase I trial was designed to determine the maximum tolerated dose (MTD) of weekly bortezomib induction combined with Y-90-ibritumomab tiuxetan in patients 18 years or older with relapsed/refractory follicular or transformed non-Hodgkin lymphoma. In addition, we assessed the tolerability of weekly bortezomib consolidation following induction therapy. Cohorts consisting of three patients each were treated with bortezomib induction at doses of 1.0, 1.3, or 1.6 mg/m2 on days 1, 8, 15, and 22, rituximab 250 mg/m2 on days 8 and 15, and Y-90 ibritumomab tiuxetan 0.4 mCi/kg on day 15. Consolidation, consisting of bortezomib 1.6 mg/m2 weekly on days 1, 8, and 15 of three 28 day cycles, was initiated on day 71 after recovery of the platelet count to 100,000/uL and ANC> 1,000/uL. At least three patients per cohort were followed for 7 weeks or had recovery of blood counts without dose-limiting toxicities (DLTs) before dose escalation was allowed. MTD was defined as the dose previous to that in which two patients had DLTs. To be evaluable, patients were required to have received at least two doses of bortezomib and the Y-90-ibritumomab tiuxetan therapeutic dose. Response was assessed by CT scanning following induction therapy and PET/CT and diagnostic CT scans after completion of consolidation. Results: Nine patients with a median age of 55 (range: 29–71) were treated with bortezomib combined with Y-90-ibritumomab tiuxetan. Eight patients had FL and one had evidence of a transformation to diffuse, large B-cell lymphoma. All had a performance status of 0 or 1, and all had been previously treated with rituximab either as a single agent or in combination with chemotherapy. All but one had received prior chemotherapy [R-CHOP (n=7), chlorambucil (n=1), or R-CVP (n=2)], and three had received radiotherapy. Only one had bone marrow involvement. The median number of prior therapies was one (range: 1–3). Grade 3 or 4 toxicities were observed in all but one of the patients and as expected, all but one of these toxicities were hematologic (leukopenia, lymphopenia, neutropenia, and/or thrombocytopenia). One patient had grade 3 cardiotoxicity characterized by palpitations and shortness of breath on day 15 of her first consolidation, with PVC's noted on subsequent EKG. Though uncommon, cardiotoxicity has been reported in association with bortezomib in the form of systolic heart failure, arrhythmias, and angina. It should be noted that this patient was previously treated with an anthracycline as have the majority of patients reported to have experienced cardiotoxicity in association with bortezomib. A DLT of grade 4 thrombocytopenia lasting more than ten days was observed in two of three patients treated with bortezomib at 1.6 mg/m2. One of these two patients was the only one to receive .3 mCi/kg rather than .4 mCi/kg of the radioisotope because of thrombocytopenia on the day of treatment. Thus, the MTD of bortezomib was 1.3 mg/m2. All patients are alive, and the median followup for those patients who have not progressed is 6.5 months (range: 3 – 15 mo.). All but one patient responded to therapy (4 CR/CRu, 4PR, 1 SD). The four complete responders remain in remission at 3.0, 5.0, 5.0 and 15.0 months. All of the partial responders have progressed (3.5, 3.5, 11.5, and 17.5 months), as has the patient with stable disease (5.0 months). Conclusions: The MTD for weekly bortezomib combined with Y-90 ibritumomab tiuxetan induction therapy is 1.3 mg/m2. Consolidation with bortezomib at 1.6 mg/m2 was well tolerated in this group of relapsed/refractory follicular and transformed non-Hodgkin lymphoma patients. Nearly all patients responded. A phase II trial at the MTD is underway to better define the toxicity and effectiveness of this regimen in patients with relapsed/refractory FL. Disclosures: Evens: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ziopharm: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Ortho- Biotec: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gordon:Cure Tech, Ltd: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Inc: Research Funding; Genentech: Speakers Bureau; Millenium: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees. Winter:Millenium: Consultancy, Research Funding; Pfizer/Wyeth: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Spectrum: Honoraria.

Safety of Subcutaneous Administration of Rituximab during the First-Line Treatment of Patients with Non-Hodgkin Lymphoma: The MabRella Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2971-2971 ◽  
Author(s):  
Carlos Panizo ◽  
Mohamed Amine Bekadja ◽  
Balkis Meddeb ◽  
Maria Rigoroso Mendoza ◽  
Matt Truman ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
North Africa ◽  
Safety Profile ◽  
B Cell Lymphoma ◽  
First Line ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Background: Rituximab, administered intravenously (IV), is the mainstay of treatment for CD20+ B-cell non-Hodgkin lymphoma (NHL). A subcutaneous (SC) formulation has been approved in Europe and other countries based on the SABRINA study, which showed non-inferior pharmacokinetics and comparable safety and efficacy for rituximab SC compared with IV in treatment-naïve patients with follicular lymphoma (FL) (Davies A, et al. Lancet Oncol 2014;15:343-52). Furthermore, rituximab SC reduces healthcare resource burden (De Cock et al. PLoS One 2016;11:eD157957) and improves patient satisfaction and convenience compared with IV (Rummel et al. Blood 2015;18:A469). MabRella is a global umbrella study comprising three local open-label, single-arm, Phase 3b studies evaluating the safety of first-line (1L) rituximab SC treatment in patients with FL or diffuse large B-cell lymphoma (DLBCL) with a focus on administration-related reactions (ARRs). The studies share a core protocol, study endpoints, and timepoints, but have flexibility for modifications at local level. Data from participating countries is pooled for pre-defined global analyses. Methods: Patients were aged 18-80 years with grade 1-3a FL or DLBCL, and ECOG PS of ≤3. All patients had received ≥1 full dose of rituximab IV as 1L induction or maintenance prior to study entry, and were eligible to receive at least 4 additional cycles of induction or 6 additional cycles of maintenance. Patients with FL or DLBCL receiving induction therapy were treated with rituximab SC 1400mg every cycle (14, 21, or 28 days) for 4-7 cycles, in combination with standard chemotherapy. FL patients undergoing maintenance treatment received single-agent rituximab SC 1400mg every 2 months for 6-12 cycles. The primary endpoint was incidence of ARRs following multiple doses of rituximab SC; ARRs were defined as all adverse events (AEs) occurring within 24 hours of rituximab administration and considered related to the study drug by the investigator. Secondary safety endpoints included grade ≥3 AEs and serious AEs (SAEs). The safety analysis included all patients who received ≥1 dose of study treatment. Safety data were not collected for rituximab IV, as patients entered the trial after they had switched to SC. Data are presented from a planned interim analysis of safety (cut-off March 31, 2016). Results: At the data cut-off, the safety population comprised 336 patients: 157 from Italy; 139 from Spain; and 40 from North Africa (Tunisia and Algeria). The median (range) age was 59 (19-80) years and 50% patients were male; 205 patients had FL and 131 had DLBCL. With respect to patients with FL, 84 completed ≥1 cycle of rituximab SC induction (37 completed all 7 cycles) and 190 completed ≥1 cycle of maintenance (169 completed 6 cycles and 26 completed all 12 cycles). Among DLBCL patients, 37 completed all 7 cycles of induction. Overall, 282 patients (84%) experienced an AE during treatment (Table 1). ARRs were observed in 75 patients (22%), the most common of which (≥2% incidence) were erythema (12%) and injection-site erythema (4%). Other AEs reported in ≥10% of patients were neutropenia, asthenia, erythema, pyrexia, and diarrhea (Table 1). Grade ≥3 AEs occurring in ≥5% of patients were neutropenia (24%) and febrile neutropenia (6%). Grade ≥3 ARRs were observed in 4 patients (1%). SAEs were reported in 29% of patients (8% drug-related). Of 11 deaths attributed to AEs, 2 were considered to be related to treatment (Klebsiella infection and sepsis). The safety profile of rituximab SC was generally comparable between FL and DLBCL patients, although neutropenia (any grade and grade ≥3) was more prevalent in DLBCL patients, while erythema (any grade) was more common in FL patients (Table 1). The profile of AEs was similar during induction and maintenance, but the intensity and seriousness of events was lower during maintenance (Table 2). Geographic location (Spain, Italy, North Africa) of study sites did not appear to impact on the safety profile of rituximab SC. Conclusions: In line with previous reports (Davies et al. 2014), rituximab SC is well tolerated during the 1L treatment of patients with NHL. The safety profile of 1L rituximab SC is similar to reports for IV administration, with the exception of an expected increase in ARRs, the majority of which are mild or moderate in intensity, and resolve spontaneously. Disclosures Panizo: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Speakers Bureau. Rigoroso Mendoza:F Hoffmann La Roche Ltd: Employment. Truman:Aurinia Pharmaceuticals: Consultancy; F Hoffmann La Roche Ltd: Consultancy, Equity Ownership. Smith:F. Hoffmann La Roche Ltd.: Employment.

Phase 1 Dose-Escalation Study of MLN4924, a Novel NAE Inhibitor, in Patients with Multiple Myeloma and Non-Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1854-1854 ◽  
Author(s):  
Jatin J Shah ◽  
Andrzej J Jakubowiak ◽  
Owen A O’Connor ◽  
Robert Z Orlowski ◽  
Molly Patterson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Whole Blood ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Abstract 1854 Poster Board I-880 Background: MLN4924 is a first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE), an essential component of the NEDD8 conjugation pathway in the ubiquitin-proteasome system. Inhibition of NAE with MLN4924 prevents conjugation of NEDD8 to the Cullin Ring Ligases (CRLs). This subsequently prevents ubiquitination and proteasomal degradation of CRL substrates, which include proteins involved in cell cycle regulation (p27), signal transduction (pIκBá), DNA replication (Cdt-1), stress response (Nrf-2), and other processes important to tumor cell growth and survival. MLN4924 has demonstrated potent antitumor activity in vitro against multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines as well as in mouse xenograft models of NHL. This phase 1 dose-escalation study is the first investigation of MLN4924 in MM or NHL patients (pts). The primary objectives were to determine the maximum tolerated dose (MTD) and safety profile of MLN4924, describe the pharmacokinetics (PK) and pharmacodynamics (PD) in blood (inhibition of NEDD8-Cullin levels in peripheral blood mononuclear cells [PBMCs]; Nrf-2 target gene transcription in whole blood), and investigate PD effects in skin (Cdt-1, Nrf-2 accumulation). Methods: Pts aged ≥18 yrs with relapsed and/or refractory MM or NHL after ≥2 prior lines of therapy were eligible. Pts received escalating doses of MLN4924 by IV infusion on days 1, 2, 8, and 9 of 21-day cycles; once the MTD for this schedule was reached, MTDs for other schedules will be investigated. MTD determination was based on an adaptive approach using a Bayesian continual reassessment method, with the MTD defined as the dose level closest to that predicted to result in a dose-limiting toxicity (DLT) rate of 25%. DLT was defined as: grade 4 neutropenia or thrombocytopenia for >7 days; grade 3 neutropenia with fever/infection or thrombocytopenia with bleeding; grade ≥3 non-hematologic toxicity except arthralgia/myalgia, brief fatigue, or fever without neutropenia; and grade ≥2 MLN4924-related toxicities requiring dose reduction/discontinuation. For PD analysis, PBMCs and whole blood were isolated at screening, baseline, and following MLN4924 administration; skin biopsies for Cdt-1 and Nrf-2 assays were performed at baseline and after the second dose. Results: Among 22 pts enrolled to date, median age was 65 years, 13 were male, 14 had MM, and 8 had NHL (4 FL, 1 MCL, 1 DLBCL, 1 B-cell CLL/SLL, 1 transformed CLL). All MM pts had received prior autologous SCT, and 13, 9, and 9 had prior bortezomib, lenalidomide, and thalidomide, respectively. Seven NHL pts had received prior autologous SCT, 1 had a prior allogeneic SCT, and 8 had prior rituximab. Pts received MLN4924 at 6 dose levels: 25 (n=3), 50 (n=2), 65 (n=3), 83 (n=2), 110 (n=9), and 147 mg/m2 (n=3). Of the 15 (68% of the 22 enrolled) pts who received all 4 scheduled doses or had a DLT in cycle 1 (DLT-evaluable pts), 4 experienced a DLT: 1 grade 4 febrile neutropenia at 65 mg/m2; 1 grade 3 liver function tests at 110 mg/m2, and 1 grade 4 muscle cramps and 1 grade 2 myalgia that was considered dose limiting at 147 mg/m2. Thus, the MTD for this schedule was determined to be 110 mg/m2. The most common adverse events (AEs, NCI CTCAE v3.0) included fatigue, nausea, myalgia, and elevated liver enzymes. With the exception of the grade 4 neutropenia seen at 65 mg/m2, myelosuppression was limited. No infusion-related reactions were noted. Elevated CRP levels appeared transient in most cases. There have been no treatment-related deaths; 1 MM pt died due to progressive disease. MLN4924 displayed a multiexponential PK profile with a half life of 4–9 hours, relatively low PK variability, and approximately dose-proportional increases in total plasma exposure over the 25–147 mg/m2 dose range. NEDD8-Cullin levels in PBMCs were inhibited and Nrf-2 target gene transcripts in whole blood were higher vs baseline after MLN4924 administration, indicative of NAE inhibition. Cdt-1 and Nrf-2 levels in skin increased above baseline following the second dose of MLN4924, indicative of NAE inhibition in peripheral tissue. The 110 mg/m2 dose level is being expanded to more fully characterize safety, PK, and PD in MM and NHL. Subsequent pts will be enrolled to receive MLN4924 on 2 other schedules. Conclusions: This early analysis provides evidence of PD inhibition of NAE activity by MLN4924 in blood and skin, and supports continued investigation of MLN4924. Disclosures: Shah: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Elan: Consultancy; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: MLN4924 is not approved for the treatment of multiple myeloma or non-Hodgkin lymphoma.. Jakubowiak:Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berger:Millennium Pharmaceuticals, Inc.: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Petruzzelli:Pfizer: Equity Ownership; Millennium Pharmaceuticals, Inc.: Employment; Amgen: Equity Ownership. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Smith:Millennium Pharmaceuticals, Inc.: Employment. Venkatakrishnan:Millennium Pharmaceuticals, Inc.: Employment. Lonial:Novartis: Consultancy; Gloucester: Research Funding; BMS: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy.

A Phase II Multi-Center Trial Of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) In Older Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4177-4177 ◽  
Author(s):  
Marco Montillo ◽  
Davide Rossi ◽  
Marina Motta ◽  
Giulia Quaresmini ◽  
Marianna Rossi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Free Survival ◽  
Grade 3 ◽  
Anti Cd20

Abstract Introduction The seminal phase 3 trial conducted by the German CLL Study Group demonstrated that the addition of the anti-CD20 monoclonal antibody [mAb] rituximab to the FC platform (FCR) improved response rates, progression free survival and also overall survival. However, FCR showed considerable hematologic toxicity, particularly among patients over age 70. Pentostatin demonstrated similar response frequency to other purine analogues in CLL. Furthermore, its relative lack of myelotoxicity has allowed to use it with improved tolerability particularly when administered in combination with myelotoxic agents such as cyclophosphamide. Ofatumumab is a fully human anti-CD20 mAb with clinical activity as a single agent in patients with fludarabine-refractory CLL. Ofatumumab appears to have greater single agent clinical activity than rituximab in patients with previously treated CLL and also has activity in rituximab-refractory patients. Given the reported efficacy of chemo immunotherapy [CIT] in CLL and the activity and toxicity profile of pentostatin combinations, we designed a trial of pentostatin, cyclophosphamide, and Ofatumumab for previously untreated older patients with CLL. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) aged ≥ 65 years and ECOG PS of 0-2 were enrolled to receive Pentostatin 2 mg/sqm and Cyclophosphamide 600 mg/sqm both as intravenous infusions at day 1 of each 21 day cycle and Ofatumumab administered as intravenous infusions (Cycle 1: 300 mg day 1 and 1000 mg day 2, subsequent cycles: 1000 mg at day 1). Ofatumumab premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was of 6 cycles. The primary endpoint was overall response rate (ORR) including detection of minimal residual disease (MRD) and secondary endpoints included, progression-free survival (PFS) overall survival (OS) and safety. Patients 49 patients from 12 centres from the italians regions of Lombardy and Piedmont were included. Baseline demographics were: Median age 72.8 years with 64% aged over 70, among them 32 were males (65%). Disease characteristics in 32 patients evaluable at this point were: 76% Binet stage B and 24% C; 45% of patients had unmutated IGVH, 7 % showed 17p deletions. Results ORR was 93.7% with 41% CR(11)/CR(2) with incomplete marrow recovery [CRi]. All six intended courses of treatment were administered to 30 (94%), and 90% of these patients received full-dose treatment. The reason for discontinuing treatment before completing six courses was myelosuppression occurring in 2 patients. The primary reason for dose reduction was again myelosuppression. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 62% of patients receiving PCO with the most common being neutropenia [Total number of patients with at least one Grade 3 or 4 event: 19 patients] while anemia and thrombocytopenia were detected only as grade 1 to 2 in 41% and 25% of cases respectively. Of the grade 1 to 2 toxicities, fever occurred in 2 patients (6%), hypotension occurred in 2 patients (6%), nausea and vomiting occurred in 3 patients (9%), skin rash of grade 1 occurred in 2 patients. Grade 3 infusion-related AEs were reported in 12% of patients. There were no grade 4 toxicities associated with any Ofatumumab infusion. Grade 3 infection was reported in 1 patient (3%) being a pneumonia. No deaths during treatment occurred in these 32 subjects. Conclusion Ofatumumab added to Pentostatin and Cyclophosphamide demonstrated clinically important results and is well tolerated in patients with previously untreated CLL. In this preliminary report the efficacy of this ofatumumab-based CIT compares favorably to the historical rituximab-based CIT using the same chemotherapeutic agents with a more manageable side effect profile in this older population. Further data in a higher number of enrolled patients and including MRD detection will be presented at the Meeting. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

Pevonedistat (MLN4924), an Investigational, First-in-Class NAE Inhibitor, in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML) Considered Unfit for Conventional Chemotherapy: Updated Results from the Phase 1 C15009 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2313-2313 ◽  
Author(s):  
Ronan T Swords ◽  
Michael R Savona ◽  
Michael B Maris ◽  
Harry P Erba ◽  
Jesus G. Berdeja ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
De Novo ◽  
Single Agent ◽  
Clinical Activity ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
De Novo Aml ◽  
Grade 3

Abstract Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naïve AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts >80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. Table 1 Common all-grade AEs n (%) Most frequent (≥10%) drug-related grade ≥3 AEs n (%) Febrile neutropenia 9 (36) Febrile neutropenia 4 (16) Constipation 8 (32) Thrombocytopenia 3 (12) Decreased appetite 7 (28) – – Thrombocytopenia 7 (28) – – Table 2 Responders* Tumor Type Cytogenetic Risk Group Current Status Response Molecular CR 1st Response 1st CR 1 De novo AML Adverse C12 C4 – – 2 Undetermined C4† C1 C1 Y 3 Adverse C9 C1 C1 Y 4 Undetermined C5‡ C1 C2 Y 5 Intermediate C5† C1 C2 N 6 Intermediate C7 C1 C4 Y 7 Intermediate C2 C2 – – 8 Secondary AML Undetermined C4 C2 C2 – 9 Normal C4 C1 – – 10 De novo AML – C1 C1 – – Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran:Takeda Pharmaceuticals International Co.: Research Funding. Hua:Takeda Pharmaceuticals International Co.: Employment. Faessel:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash:Takeda Pharmaceuticals International Co.: Employment. Sedarati:Takeda Pharmaceuticals International Co.: Employment. Dezube:Takeda Pharmaceuticals International Co.: Employment. Medeiros:Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

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.

A Phase I Study of a Combination of 5-Azacyitidine Followed by Lenalidomide In High-Risk MDS or AML Patients with Chromosome 5 Abnormalities – Interim Results of the “AZALE” Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4000-4000 ◽  
Author(s):  
Uwe Platzbecker ◽  
Detlef Haase ◽  
Friederike Braulke ◽  
Gesine Bug ◽  
Katharina Götze ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Single Agent ◽  
Rapid Progression ◽  
Chromosome 5 ◽  
Advisory Committees ◽  
Cytogenetic Remission ◽  
Grade 3 ◽  
Ongoing Phase

Abstract Abstract 4000 Lenalidomide has shown single agent activity in patients with MDS (Myelodysplastic Syndromes) and a del(5q) cytogenetic abnormality. Further, studies with the DNA methyltransferase inhibitor 5-azacytidine (5-aza) have been conducted in high-risk MDS (IPSS INT-2 or HIGH) and patients with acute myeloid leukemia (AML) resulting in considerable responses with a low rate of extramedullary toxicity compared to conventional induction chemotherapy (IC). Given the poor outcome of high-risk MDS and AML patients with chromosome 5 abnormalities, there is a significant clinical need to perform studies with new regimens in this patient population. We report first results of an ongoing phase I clinical trial evaluating the maximum tolerated dose (MTD) of lenalidomide in combination with 5-aza in patients with either high-risk MDS, refractory/relapsed AML or de novo AML not eligible for conventional IC with chromosome 5 abnormalities including monosomy 5 or del(5q). Given the mechanism of action of both drugs and also in contrast to a recent study in non-del(5q) MDS patients, a sequential approach was chosen. In fact, induction therapy consisted of 5-aza (75mg/m2 days 1–5) followed by increasing doses of lenalidomide (starting with 10mg p.o., days 6–19). In patients achieving a complete remission this was followed by a combined maintenance therapy every 8 weeks until disease progression. To determine the MTD, a standard “3+3” design was used. The dose limiting toxicity (DLT) is determined during the first cycle only and is defined as either inability to deliver the full dosing schedule of lenalidomide due to any ≥ Grade 3 non-hematologic toxicity or absence of hematological recovery after completing the 1st cycle despite complete marrow blast clearance or treatment delay of ≥ 4 weeks as a result of unresolved grade 4 non-hematological toxicity. Of 8 patients currently enrolled, median age was 67 years (range, 45 to 74 years), interval from primary MDS or AML diagnosis was 9 months (range, 1 to 100 months). IPSS categories were INT-2 (n = 1) and HIGH (n = 3) whereas 4 patients were included with advanced AML. It is of note, that all but two patients had a complex karyotype including a del(5q) abnormality. Prior treatment included IC (n=1), IC plus allogeneic HSCT (n=3) and/or single agent 5-aza (n=3) while 4 patients had received supportive care only prior to study entry. A median of 2 induction cycles were administered. During the first cycle of cohort I (10mg lenalidomide) and cohort II (15mg lenalidomide) grades 3 to 4 non-hematologic toxicities included febrile neutropenia (n = 3), enterocolitis (n = 1) and pneumonia (n=3) whereas therapy-induced grade 3–4 neutropenia or thrombocytopenia occurred in four and five patients, respectively. The MTD has not been reached yet. One patient (12.5%) with AML showed rapid progression while receiving the 1st cycle. Out of the remaining seven patients, one (12.5%) achieved a marrow CR together with a partial cytogenetic remission, and six patients (75%) had stable disease. Interestingly, two out of these achieved a partial cytogenetic remission. These preliminary data of an ongoing phase I trial demonstrate the safety and the potential of a combination of 5-aza and lenalidomide in patients with advanced MDS or AML and a del(5q). Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hofmann:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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