Introduction: Rituximab (R) plus chemotherapy (chemo) is standard of care for patients (pts) with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). A subcutaneous (SC) formulation ...of R (R-SC) that has a non-inferior pharmacokinetic profile to the intravenous (IV) formulation (R-IV) and similar efficacy and safety in DLBCL and FL pts is now available for clinical use. The randomized, open-label, crossover, Phase 3b PrefMab study (NCT01724021) aimed to explore pt preference and treatment satisfaction for the SC vs IV formulation of R. In the primary analysis (data cut-off, January 19, 2015; Rummel et al. Ann Oncol 2017), a strong pt preference for R-SC over R-IV administration was demonstrated (81% vs 11% at Cycle 8; primary endpoint). In addition, on the Rituximab Administration Satisfaction Questionnaire, median scores were higher for R-SC vs R-IV for ‘Impact on Activities of Daily Living’, ‘Convenience of Therapy’, ‘Satisfaction with Therapy’, and ‘Psychological Impact’. No new safety signals were reported. Here, we present the final analysis of the PrefMab study, which was performed after all pts had completed at least 24 months' follow-up (data cut-off, December 20, 2016) with a focus on long-term pt outcomes and safety.
Methods: Pts aged 18-80 yrs with previously untreated CD20+ DLBCL or FL were randomized 1:1 to receive one of two 8-cycle schedules of R in combination with 6-8 cycles of chemo (CHOP, CVP, or bendamustine, as per local practice): Sequence A (n=372), 1 cycle R-IV (375mg/m2) then 3 cycles R-SC (1400mg) then 4 cycles R-IV; Sequence B (n=371), 4 cycles R-IV then 4 cycles R-SC. Maintenance therapy was not mandated by the study protocol; however, pts with FL could receive maintenance at the investigator's discretion. Secondary endpoints reported here include overall (OR) and complete response (CR) rates (assessed according to Cheson 1999 criteria) and investigator-assessed progression-free (PFS), event-free (EFS), disease-free, and overall survival. Safety was also assessed by treatment-emergent adverse event (AE) reporting. Efficacy was analyzed in all randomized pts, safety in all pts who received ≥1 dose of R.
Results: Of 743 randomized pts, 740 received study treatment (465 pts with DLBCL 63%, 273 with FL 37%, and 2 other 0.3%). Demographics and baseline characteristics are presented in Table 1. The median age of pts with DLBCL was 61 yrs and of pts with FL was 59 yrs. The majority of pts with DLBCL and FL received CHOP chemo (Table 1). OR rates were >90% in both DLBCL and FL pts (Table 2). CR rates were 55.1% in pts with DLBCL and 44.4% in pts with FL (Table 2). PFS rates at 3 yrs were 79% in DLBCL pts and 91% in FL pts. Other time-to-event endpoints are presented in Table 2. EFS was shorter in FL pts than DLBCL pts; however, because R maintenance was considered a non-protocol-specified anti-lymphoma therapy, FL pts were censored at the time of starting maintenance therapy. Treatment sequence had no impact on response rates or time-to-event endpoints. Pharmacokinetic serum-level data will be presented.
Of pts who received ≥2 cycles of treatment, 653/712 (92%) experienced ≥1 AE on or after Cycle 2. AEs were generally balanced according to administration route and diagnosis, although a higher rate of grade ≥3 AEs and serious AEs occurred in DLBCL pts compared with FL (Table 3). Most AEs occurred in Cycle 1, during which all pts received R-IV (pts with AE in Cycle 1: Arm A, 71%; Arm B, 69%). No administration-related reactions (ARRs) occurred at a frequency of ≥2% in pts receiving
R-SC or R-IV on or after Cycle 2. There were no differences in rates of ARRs according to IV or SC administration. FL pts were more likely to experience an ARR than DLBCL pts. At the end of the study, 104 pts had died (85 DLBCL; 19 FL). Fatal AEs related to R, according to the investigator's judgment, included oropharyngeal candidiasis, pneumonia, septic shock, febrile neutropenia, and myocardial infarction (1 case each).
Conclusions: In addition to the strong pt preference for SC dosing and improved satisfaction observed in the primary analysis, these findings confirm that R-SC is an efficacious and well-tolerated treatment option in DLBCL and FL pts. Overall, outcomes did not appear to be impacted by treatment sequence.
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Rummel:Roche: Honoraria, Other: PrefMab is sponsored by F. Hoffmann-La Roche Ltd. Third-party Medical Writing assistance, under the direction of Mathias Rummel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Brugger:AstraZeneca: Employment, Equity Ownership. Re:Gilead: Membership on an entity's Board of Directors or advisory committees. Task:Genentech: Employment, Equity Ownership. McIntyre:Roche: Employment, Equity Ownership. Meier:Roche: Employment. Osborne:Roche: Employment. Smith:Roche: Employment. Grigg:Roche: Other: Funding to attend ASH 2016.
Background: Aurora kinases represent potential targets for anticancer therapy in solid tumors and hematological malignancies. In a phase I/II study, the aurora B kinase inhibitor AZD1152 (barasertib) ...showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811 nanoparticle is a novel, encapsulated slow-release inhibitor of Aurora kinase B offering several advantages compared with AZD1152, including prolonged drug release in vivo. AZD2811 nanoparticle mimics the AZD1152 7-day continuous infusion when given as a 2-hr infusion on Day 1 and 4, and resulted in increased efficacy and decreased toxicity in vivo. We report the first-in-man dose-escalation of AZD2811 nanoparticle in pts with relapsed AML/MDS or treatment-naïve patients not eligible for intensive induction therapy. The objectives were to determine the safety profile, MTD, PK, dosing schedule and preliminary efficacy of AZD2811 nanoparticle. Methods: Patients received a single 2-hour IV infusion on Day 1 and 4 of each 28-day cycle. Based on the previous experience with AZD1152 in the same patient population, the expected MTD is in a range of 1,200 mg per cycle. In the ongoing dose escalation, cohorts of 3-6 patients have been sequentially enrolled in 4 cohorts ranging from 100 mg to 600 mg per infusion on Day 1 and 4 every 28 days, i.e. from 200 mg to 1,200 mg per cycle. Patients were allowed to continue to receive AZD2811 until disease progression, tolerability, or discontinuation criteria have been met. The study uses a Bayesian adaptive design approach to dose escalation to improve the efficiency and precision of the MTD estimation compared to a traditional 3+3 design. Results: Currently, 10 pts with age ranges from 56 to 86 years have completed DLT assessment period for the first 3 cohorts. 9 patients had relapsed/refractory secondary AML/MDS after failure of hypomethylating agents and 1 patient had a relapsed, therapy-related AML. Cohort 4 (600 mg per infusion D1 and D4) is currently under evaluation. Of the 10 pts in cohorts 1-3, 7 pts discontinued due to disease progression, 1 discontinued due to subject decision/consent withdrawal, 1 discontinued due to physician decision, and 1 pt is active and ongoing. AEs assessed as related to AZD2811 that occurred in one or more patients were Grade 3/4 neutropenia/thrombocytopenia, Grade 3 anemia and Grade 1 fatigue, rash and stomatitis. Thus far, no DLTs and no fatal AEs related to AZD2811 have been observed. 2 deaths have been reported, 1 due to the underlying disease and 1 due to a Serious Adverse Event of Gr 5 Sepsis (not related to study drug). AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours. Conclusion: AZD2811 nanoparticle is safe and well tolerated at a dose up to 400 mg on Day 1 and 4 every 28-days. The monotherapy dose escalation is ongoing and updated results including preliminary efficacy data and supporting preclinical data will be presented. Additional dose finding and expansion cohorts of AZD2811 nanoparticle in combination with azacytidine and venetoclax are planned.
Atallah:Novartis: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Jazz: Consultancy; Pfizer: Consultancy. Charlton:AstraZeneca: Employment. MacDonald:AstraZeneca: Employment. Young:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment. Overend:AstraZeneca: Employment. Adelman:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment. Pease:AstraZeneca: Employment. Brugger:AstraZeneca: Employment.
Summary
The combination of lenalidomide (Revlimid®, R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small ...fraction of patients will achieve high quality responses ≥ very good partial response (VGPR). The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose‐limiting haematotoxicity restricted its use in extensively pre‐treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years range 46–83) and were treated with B 75 mg/m2 days 1, 2; R 25 mg days 1–21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28‐day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol‐defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.
Advanced follicular and mantle cell lymphoma are currently incurable using conventional chemotherapy. As such, new and potentially more effective therapeutic approaches such as high-dose chemotherapy ...with autologous stem cell transplantation (ASCT) and consolidation using various types of therapy are being increasingly considered. Rituximab has been assessed as an in vivo purge and as consolidation therapy both first-line and in relapsed patients with follicular and mantle cell lymphoma. Data from a number of studies are reviewed, focusing on our recently reported phase II study of patients with follicular or mantle cell lymphoma who received one standard course of rituximab consolidation therapy after ASCT to show that using rituximab in the context of high-dose chemotherapy and ASCT may improve patient outcomes without compromising tolerability. Specifically, purging and consolidation using rituximab can improve clinical and molecular response rates, may eliminate minimal residual disease, and may improve survival. These studies suggest that rituximab may have an important role in improving the outcome of ASCT in patients with follicular or mantle cell lymphoma.
Introduction: Patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have a poor outcome ...and are difficult to treat. This ongoing, two-cohort, Phase II trial evaluates the safety and preliminary efficacy of tafasitamab (MOR208), an Fc-enhanced anti-CD19 monoclonal antibody in combination with idelalisib (IDE) (Cohort A) or venetoclax (VEN) (Cohort B) in R/R CLL pts previously treated with a BTKi. Preliminary results were published at EHA 2018 for Cohort A and at ASH 2018 for Cohort B. Here, we report the results of the primary analysis for both cohorts.
Methods and Patients: Pts who either progressed or were intolerant to BTKi were enrolled at 12 sites in six countries in Europe and the US from Nov 2016 to Apr 2018. The primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to International Workshop on CLL (IWCLL) 2008 guidelines. Complete response (CR) was confirmed by computed tomography assessment and by bone marrow (BM) biopsy. The exploratory endpoint minimal residual disease (MRD) was assessed centrally by quantitative allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and BM. Each treatment cycle (C) lasts 28 days (D). Dose and administration: tafasitamab intravenous infusion, 12 mg/kg weekly in C1-C3, every other week in C4-C6 and monthly from C7D1; IDE orally, 150 mg twice daily; VEN orally, weekly ramp up starting on C1D8 at 20 mg to full daily dose of 400 mg. Patients: mean time since first CLL diagnosis was 135 months (mos) for pts in Cohort A and 105 mos in Cohort B. Median number of prior therapy lines was five (2-9) and three (1-5), respectively. All pts had received ibrutinib; one pt had subsequent acalabrutinib treatment as last prior therapy line. Mutations of BTK and PLCγ2 were assessed in nine pts in Cohort A and 13 pts in Cohort B. BTK/PLCγ2 mutations were centrally detected in 4/3 pts in Cohort A and in 2/3 pts in Cohort B, respectively. Complex karyotype was observed in six (54.5%) pts in Cohort A and 12 (92.3%) pts in Cohort B. Results with a data cut-off date of 9 Nov 2018 are presented.
Results:
Cohort A: Median time on study was 9.9 mos (95% confidence interval CI: 5.7-not reached). Eleven pts were enrolled and received tafasitamab and IDE. Two pts discontinued treatment due to AEs (aspartate-aminotransferase increased; acute pancreatitis), two due to progressive disease (PD) and one pt by physician's decision. One pt died due to PD and one pt due to cardiac failure. At the cut-off date, treatment was ongoing in four pts. Table 1 summarizes treatment-emergent adverse events (TEAEs) with neutropenia Grade ≥3 being most common (5 46%). Fourteen treatment-emergent serious AEs (SAEs) were reported in eight (72.7%) pts. ORR was 90.9% (CR=9.1%, partial response PR=81.8%), disease control was achieved in all 11 pts. One of eight pts (12.5%) assessed for MRD status reached MRD-negativity in PB at C14.
Cohort B: Median time on study was 12 mos (95% CI: 2.8-not reached). Eleven of 13 enrolled pts received tafasitamab and VEN while two pts received tafasitamab only. Three pts discontinued treatment due to AEs (infusion-related reactions two pts, diarrhea one pt, one due to PD and one withdrew consent. At the cut-off date, treatment was ongoing in eight patients. Table 2 summarizes TEAEs, neutropenia Grade ≥3 was most commonly observed (six 46% pts). Fourteen SAEs were reported in nine (69.2%) pts. The ORR in all 13 pts was 76.9% (CR=23.1%, PR=53.8%, not evaluable=23.1%). Six of seven pts assessed for MRD in PB (46.2% of 13 100% pts) reached negative status in PB by C7 at the latest. One of three pts assessed for MRD in BM (7.7% of 13 100% pts) reached MRD negative status in BM at C15.
Conclusions: This trial demonstrates that in heavily pretreated pts with R/R CLL who failed prior BTKi, tafasitamab in combination with IDE or VEN is a potential therapeutic option. The safety profiles of the combinations are influenced by the combination partner, but both combinations are manageable. The response rates and MRD-negativity rates indicate that combinations of targeted agents with anti-CD19 tafasitamab have valuable antitumor activity and warrant further investigation of tafasitamab-based combinations in CLL.
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Staber:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: 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, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene Corporation: Research Funding; Incyte: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Brugger:AstraZeneca: Equity Ownership; MorphoSys: Employment. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Xencor: Research Funding; AbbVie: Research Funding. Greil:Mundipharma: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Sandoz: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Janssen-Cilag: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Middeke:Janssen: Consultancy, Speakers Bureau; MSD: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Roche: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Montillo:Roche: Consultancy, Honoraria, Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees. Munir:Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: TBC; AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy. Parikh:Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; MorphoSys: Research Funding; Acerta Pharma: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weirather:MorphoSys: Employment. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
A phase I trial was conducted to evaluate the feasibility, safety, and efficacy of a dendritic cell-based vaccination in patients with metastatic renal cell carcinoma (RCC). Autologous mature ...dendritic cells derived from peripheral blood monocytes were pulsed with the HLA-A2-binding MUC1 peptides (M1.1 and M1.2). For the activation of CD4(+) T-helper lymphocytes, dendritic cells were further incubated with the PAN-DR-binding peptide PADRE. Dendritic cell vaccinations were done s.c. every 2 weeks for four times and repeated monthly until tumor progression. After five dendritic cell injections, patients additionally received three injections weekly of low-dose interleukin-2 (1 million IE/m(2)). The induction of vaccine-induced T-cell responses was monitored using enzyme-linked immunospot and Cr release assays. Twenty patients were included. The treatment was well tolerated with no severe side effects. In six patients, regression of the metastatic sites was induced after vaccinations with three patients achieving an objective response (one complete response, two partial responses, two mixed responses, and one stable disease). Additional four patients were stable during the treatment for up to 14 months. MUC1 peptide-specific T-cell responses in vivo were detected in the peripheral blood mononuclear cells of the six patients with objective responses. Interestingly, in patients responding to the treatment, T-cell responses to antigens not used for vaccinations, such as adipophilin, telomerase, or oncofetal antigen, could be detected, indicating that epitope spreading might occur. This study shows that MUC1 peptide-pulsed dendritic cells can induce clinical and immunologic responses in patients with metastatic RCC.
Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains ...controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. From April 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard HR, 4.28; 95% confidence interval CI, 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P = .001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335.
•Independent prognostic relevance of quantitative Bcl-2/IgH monitoring in the PB of patients with FL before and after first-line therapy.
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