scholarly journals An open-label expanded-access trial of bendamustine in patients with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT

2015 ◽  
Vol 22 (4) ◽  
pp. 260 ◽  
Author(s):  
C.T. Kouroukis ◽  
M. Crump ◽  
D. MacDonald ◽  
J.F. Larouche ◽  
D.A. Stewart ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hodgkin Lymphoma ◽  
Treatment Cycle ◽  
Day Treatment ◽  
Intravenous Dose ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Non Hodgkin Lymphoma ◽  
Post Marketing ◽  
Grade 3

BackgroundBendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non- hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). MethodsThe prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m2 over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m2 over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles.Results Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)—mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl).ConclusionsThe type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.

A Phase Ib/II Study of Combined Obinutuzumab and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4160-4160
Author(s):  
Januario E. Castro ◽  
Michael Y. Choi ◽  
Carlos I. Amaya-Chanaga ◽  
Natalie Nguyen ◽  
Amine Ale-Ali ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
High Dose ◽  
Open Label ◽  
Therapy Discontinuation ◽  
Phase Ib ◽  
Grade 3 ◽  
Anti Cd20

Abstract Chronic lymphocytic leukemia (CLL) is not curable and ultimately patients (pts) relapse and require additional treatment. In addition, most of CLL pts are older than 65 years old or are unfit to receive chemotherapy. Because of these reasons there is a need for the development of novel therapeutic strategies. Obinutuzumab, a third-generation anti-CD20 mAb, in combination with chlorambucil is currently approved by the FDA for previously untreated pts. Studies have demonstrated that most of the clinical benefit of this regimen is derived from obinutuzumab rather than chlorambucil, and also that obinutuzumab has superior clinical activity than rituximab. Because of these and our previous clinical studies that have shown synergism between HDMP and anti-CD20 antibodies, we initiated an open label phase Ib/II clinical study of obinutuzumab with HDMP for therapy of pts with CLL. The study is divided in two cohorts of 20 pts each, front-line (FL) and relapsed / refractory (RR) CLL. Pts receive HDMP 1g/m2 on Day 1-3 of cycles 1-4 (28 days / cycle) and obinutuzumab administered based on FDA dosing recommendations for 6 cycles. All pts received prophylactic medications (trimethoprim/sulfamethoxazole, acyclovir, fluconazole and allopurinol). 85% of target accrual has been completed (RR cohort=19 pts; FL cohort=15 pts). Here we present a preliminary analysis of safety /tolerability of this regimen. The median age in the RR cohort was 68 years +/- 7.8 and 62 years +/- 7.3 in the FL cohort. 84% and 87% of the pts in the RR and FL cohorts had a CIRS > 6, respectively. The median baseline absolute lymphocyte count was 32.9 +/- 32.6 x103/mm3 for pts in the RR cohort and 49.3 +/- 98.1 x103/mm3 for pts in the FL cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 32% RR vs. 0% FL, del(13q) in 63% RR vs.67% FL, del(11q) in 21% RR vs. 33% FL, and trisomy 12 in 16% RR vs. 20% FL. All 34 pts were assessed for adverse events (AEs). Most AEs were grade 1-2 (RR=88%; FL=92%) without development of dose-limiting toxicities (DLTs). One pt in the RR cohort developed asymptomatic metformin-associated lactic acidosis that required overnight inpatient observation without therapy discontinuation. Grade 1-2 obinutuzumab-infusion-related reactions (IRR) were observed in 42% and 87% of pts in the RR and FL cohort, respectively. We did not observe grade 3-4 IRR. Only one patient has required therapy discontinuation due to asymptomatic GI bleeding that required blood transfusion and resolved spontaneously. We observed neutropenia (RR: all grades: 63%, grade 3-4: 26%; FL: all grades: 53%, grade 3-4: 33%), thrombocytopenia (RR: all grades: 68%, grade 3-4: 37%; FL: all grades: 80%, grade 3-4: 40%) and anemia (RR: all grades: 58%; FL: all grades: 53%). There were no cases of febrile neutropenia. Three pts (16%) in the RR cohort developed community-acquired pneumonia, requiring outpatient treatment with oral antibiotics but not study treatment discontinuation. The most frequent non-hematological AEs were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). All 34 pts have had favorable clinical and hematological responses. Six pts (4 pts in the RR cohort and 2 pts in the FL cohort) were evaluable for response assessment by iwCLL criteria. The four pts in the RR cohort achieved a PR. In the FL cohort, 1 pt achieved a CR MRDneg (<0.01% CLL in the marrow), and the other pt achieved a PR. Overall, obinutuzumab with HDMP has been well tolerated with no evidence of DLTs. The profile of AEs appears favorable compared to those noted with obinutuzumab in combination with chlorambucil, particularly in terms of grade 3-4 IRR (0% vs 20%) or rate of therapy discontinuation (3% vs 7%). Enrollment continues and updated information will be presented during the meeting. Disclosures Choi: AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma

2016 ◽  
Vol 57 (4) ◽  
pp. 484-492 ◽  
Author(s):  
Ahmed Hamed Salem ◽  
Suresh K. Agarwal ◽  
Martin Dunbar ◽  
Sari L. Heitner Enschede ◽  
Rod A. Humerickhouse ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hodgkin Lymphoma ◽  
Lymphocytic Leukemia ◽  
Non Hodgkin Lymphoma

scholarly journals An Open-Label, Phase Ib Study of Duvelisib (IPI-145) in Combination with Bendamustine, Rituximab or Bendamustine/Rituximab in Select Subjects with Lymphoma or Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4422-4422 ◽  
Author(s):  
Ian Flinn ◽  
Manish R. Patel ◽  
Michael B Maris ◽  
Jeffrey Matous ◽  
Mohamad Cherry ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Treatment Delay ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Grade 3

Abstract Background: Duvelisib is a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) being developed as a potential therapeutic in hematologic malignancies including B and T cell lymphoma and chronic lymphocytic leukemia (CLL). In a phase I study of single agent duvelisib (D), ORR of 52% was seen in pts with indolent non-Hodgkin’s lymphoma (iNHL) and 47% in CLL. Bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with either bendamustine or rituximab alone or in combination with each other may improve response rates and the durability of remission. The goal of this Phase 1b, open-label, three-arm, non-randomized, dose escalating, safety and tolerability trial is to characterize the safety, maximum tolerated dose (MTD) and preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL. Methods: Pts had relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID up to 12 cycles. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib were explored, 25, 50, and 75 mg PO BID. DLTs were defined as: febrile neutropenia, G4 neutropenia ≥7 days, G4 thrombocytopenia ≥ 7 days or G3 thrombocytopenia with bleeding, Grade 4 AST/ALT, Grade 2 hyperbilirubinemia ≥7 days, ≥ Grade 3 non-hematologic toxicity ≥7 days (excluding alopecia), Treatment delay of ≥7 days due to unresolved toxicity that prevents re-dosing, hepatocellular injury (defined as ALT>2 x ULN and (ALT/ULN)/(ALP/ULN) >5) and bilirubin >2 x ULN or jaundice ± alkaline phosphatase <2 x ULN. Patients were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and May 2014, 32 pts, median age 66 years (44-78) were enrolled to the study, 12 NHL pts on the dose escalation portion and 20 pts on dose expansion (13 CLL, 7 NHL). Patients had a median of 4 prior therapies (1-11). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB) in which a higher dose of bendamustine is used 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). Dose escalation continues in this arm as the MTD has not reached. Patients on the dose expansion portion of the study are receiving duvelisib at 25 mg BID due to emerging data of duvelisib monotherapy showing no advantage in doses greater than 25 mg BID in these histologies. The AE profile is consistent with the toxicities of the single agents. The most common AEs > grade 3 were neutropenia (28% overall; [Arm 1 (DR), 27%]; [Arm 2 (DBR), 38%]), and rash (16% overall; [Arm 1, 14%]; [Arm 2, 25%]). Grade 3 or higher AST/ALT increases were seen in 2 out of 12 patients on Arm 1, 2 out of 8 patients on Arm 2 and no patients on Arm 3. There have been 2 deaths (cardiac arrest and pneumonia), both on Arm 1. Twenty one pts were evaluable for response with an ORR of 81% (10% CR, 71% PR, 14% SD and 5% PD). With a median follow up of 4.0 months, time to event analyses are immature. However, Kaplan-Meier estimate of PFS at 3 months is 87%. PK analysis is consistent with the monotherapy Phase I trial of duvelisib. Conclusions: Initial early analysis of duvelisib administered in combination with bendamustine and rituximab suggests these combinations to be generally well-tolerated with encouraging. Further follow-up is required to better characterize response rates and durability of remissions. Disclosures Flinn: Infinity Pharmaceuticals: Research Funding. Matous:Infinity Pharmaceuticals: Research Funding.

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