Recently, a number of devices have been developed for the positive selection of CD34(+) peripheral blood progenitor cells (PBPC) for clinical use in autologous or allogeneic transplantation. The ...rationale for CD34(+) selection is based on clinical studies showing a two- to five-log reduction of contaminating tumor cells in patients with breast cancer, multiple myeloma and low-grade lymphoma. In addition, a three- to five-log reduction of T cells can be obtained by CD34(+) selection in both autologous grafts for patients with autoimmune disease resistant to conventional therapy and allogeneic grafts to reduce the incidence and severity of acute graft-versus-host disease. Transplantation of positively selected autologous CD34(+) PBPC results in a rapid and stable neutrophil and platelet engraftment in patients who received an infused dose of at least 2.0 x 10(6) CD34(+) cells/kg. Results from randomized trials suggest that time to engraftment is not different compared to unmanipulated PBPC autografts. However, close monitoring for infectious complications (e.g., cytomegalovirus disease) is required. Allogeneic CD34(+) PBPC have also been successfully transplanted and, using novel technologies, megadoses of purified CD34(+) PBPC can be obtained and used to overcome histocompatibility differences betweeen allogeneic donor and patient resulting in stable engraftment, even in a haploidentical setting. Additional randomized phase III trials are required to determine whether tumor cell purging or lymphocyte depletion by CD34(+) cell selection will have a significant impact on progression-free and overall survival in both autologous and allogeneic transplantation.
Objective
A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double ...autologous stem cell transplantation (ASCT) on progression‐free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed.
Methods
Following induction therapy and high‐dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35‐day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation.
Results
Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P = .0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non‐existent in the bortezomib consolidation arm but pronounced in the observation arm (P = .0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P = .0569).
Conclusions
Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.
Patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) whose treatment failed with a Bruton's tyrosine kinase inhibitor have poor outcomes. We investigated tafasitamab plus ...idelalisib (cohort A) or venetoclax (cohort B) in this patient population in a phase II study (NCT02639910). In total, 24 patients were enrolled (cohort A: n = 11, median time on study, 7.4 months; cohort B: n = 13, median time on study, 15.6 months). The most common treatment-emergent adverse event (TEAE) in cohort A was anemia (63.6%) and in cohort B was infusion-related reaction (53.8%). The most common severe TEAE was neutropenia (cohort A: 45.5%; cohort B: 46.2%). The best overall response rate was 90.9% (cohort A) and 76.9% (cohort B). Undetectable minimal residual disease in peripheral blood was achieved in 2/8 patients (cohort A) and 6/7 patients (cohort B). Overall, these results suggest that anti-CD19 antibody-based combinations may be important in the treatment of patients with CLL.
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) in adults. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) remains the ...standard of care for newly diagnosed DLBCL, with cure rates of 60-70%. However, more effective front-line options are needed to further improve outcomes, particularly in high-risk patients (Sehn LH, Gascoyne RD. Blood 2015;125:22). Approximately 15-20% of treatment-naïve patients with DLBCL have CD20-low expressing tumors, while CD19 is expressed in >90% of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. Blood 2009;113:3773; Prevodnik VK, et al. Diagnostic Pathol 2011;6:33).
CD19 is a B-lymphocyte lineage-specific surface antigen that is widely expressed in mature B-cell malignancies, including DLBCL. CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation, and is, therefore, an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized anti-CD19 monoclonal antibody with an engineered constant region (Fc) that enhances Fc-γ receptor binding affinity on effector cells, thereby enhancing antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Preliminary data in DLBCL cell lines suggest that combined targeting of CD19 and CD20 with tafasitamab and rituximab, respectively, could have synergistic cytotoxic effects.
Monotherapy with tafasitamab has shown clinical activity and acceptable safety in a Phase I study in relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (NCT01161511) and in a Phase IIa study in R/R NHL (NCT01685008). In patients with R/R DLBCL, treatment with single agent tafasitamab until progression led to a 26% objective response rate (ORR) with several long-term responses (Jurczak W, et al. Ann Oncol 2018; 29:1266). Preclinical in vitro and in vivo data have demonstrated increased combinatorial antitumor effects with tafasitamab and the immunomodulatory agent lenalidomide (LEN). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, treatment with tafasitamab/LEN achieved an ORR of 60%, a complete response (CR) rate of 42.5% and a median progression-free survival (PFS) of 12.1 months (Salles GA, et al. ICML 2019; Abstr 124). This combination received breakthrough therapy designation by the US Food and Drug Administration.
Study design and methods
First-MIND is a Phase Ib, open-label, multicenter, randomized trial of tafasitamab/R-CHOP or tafasitamab/LEN/R-CHOP in patients with newly diagnosed DLBCL (Figure 1).
Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index 2-5). Key exclusion criteria include known double- or triple-hit lymphoma, and transformed or composite lymphoma.
Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously IV, on Days D 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) and LEN (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). The trial includes a safety run-in phase and a main phase. In the safety run-in phase, 12 patients will be enrolled in each arm. If no unexpected safety signals suspected to be related to the addition of tafasitamab ± LEN to R-CHOP are observed, an additional 18 patients will be enrolled in each arm in the main phase.
The primary objective of the trial is to assess safety; secondary objectives include evaluation of efficacy (ORR and PET-assessed CR rate at end of treatment, PFS, overall survival, event-free survival, time to next anti-lymphoma treatment), long-term safety and pharmacokinetics, and immunogenicity of tafasitamab in each arm. Exploratory objectives will include the assessment of biomarkers in peripheral blood (natural killer NK cell count, cell-free circulating tumor DNA) and tumor tissue (DLBCL cell of origin, NK cell or macrophage count/gene expression profile, CD19 and CD20 expression) that may be relevant to the mechanism of action and/or response to study treatment.
As this is a Phase Ib study to primarily explore safety, no formal statistical hypothesis is considered for the sample size calculation; approximately 60 patients will be recruited across Europe and the US.
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Burke:Gilead: Consultancy; Roche/Genentech: Consultancy; Celgene: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Consultancy, Research Funding; Kite: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Nowakowski:Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Rosenwald:MorphoSys: Consultancy. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Staber: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; Janssen: Honoraria, Speakers Bureau; Celgene: 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, Speakers Bureau; MSD: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trněný:Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria. Westin:Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Fingerle-Rowson:MorphoSys AG: Employment. Klanova:MorphoSys AG: Employment. Würth:MorphoSys AG: Employment. Truemper:Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Roche: Research Funding; Mundipharma: Research Funding.
Background: CD19 is broadly and homogeneously expressed across different B-cell malignancies and represents an attractive target antigen in patients with B-cell non-Hodgkin's lymphoma (NHL). ...Tafasitamab (MOR208) is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody. This ongoing study is investigating the single agent antitumor activity in adult patients with relapsed or refractory (r/r) NHL who had received at least one prior rituximab-containing therapy.
Patients and Methods: The study enrolled 92 r/r NHL patients: diffuse large B-cell lymphoma (DLBCL; n=35), mantle cell lymphoma (MCL; n=12), follicular lymphoma (FL; n=34), or other indolent NHL (iNHL; n=11). The median number of prior systemic therapies was three (range 1-15) for the entire patient population. The primary efficacy endpoint was investigator-assessed overall response rate (ORR) based on the revised International Working Group Response Criteria (Cheson et al., et al. J Clin Oncol 2007). Secondary objectives were to evaluate the time-to-response, duration of response (DoR), time to progression and progression-free survival (PFS), and to establish the safety and tolerability of tafasitamab. Patients received up to three 28-day cycles with weekly infusions of 12 mg/kg body weight of tafasitamab. Premedication, including antipyretics, histamine H1 receptor blockers and glucocorticosteroids, was administered for the first three infusions. Patients with ongoing at least partial remission (PR) at the end of Cycle 3 received further tafasitamab treatment until disease progression, either monthly or every second week.
Results: The investigator-assessed best response (intent-to-treat analysis) in the different subgroups at cut-off date (28 Sep 2018) is shown in Table 1. Five patients in complete remission (CR) (one DLBCL, two FL, two other iNHL) were ongoing and still on tafasitamab treatment at the cut-off date. These patients were on treatment for more than 4 years. The median DoR was 20.1 months in DLBCL and 24 months in FL (Table 2). The median PFS was 2.7 (95% confidence interval CI 2.1-13.2 months) and 6.6 months (95% CI 5.3-20.5 months) in DLBCL and FL, respectively. The PFS rate at 12 months was 34.3% and 39.2% for DLBCL and FL, respectively (Table 2). Similar PFS was observed in rituximab-refractory as well as non-refractory patients. Patients with a peripheral blood natural killer (NK) cell count >100 cells/µL at baseline had a median PFS of 4.2 months (DLBCL) or 8.8 months (FL/iNHL), as compared with patients who had <100 NK cells/µL at baseline showing a median PFS of 2.1 months (DLBCL) or 3.2 months (FL/iNHL), respectively. Tafasitamab was well tolerated in patients with r/r NHL. Most treatment-emergent adverse events (TEAEs) were mild in nature. The most common grade ≥3 TEAEs were neutropenia (9.8%), thrombocytopenia (4.3%), anemia (3.3%) and pneumonia (3.3%). Four patients (4.3%) experienced serious adverse reactions (febrile neutropenia, genital herpes zoster, infusion-related reaction and myelodysplastic syndrome). There was no evidence of grade ≥3 late toxicity during the long-term follow-up period; no treatment-related deaths occurred.
Conclusion: Tafasitamab monotherapy until progression resulted in durable responses and was well tolerated in patients with both aggressive and indolent NHL subtypes.
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Jurczak:Celgene: Research Funding; Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Servier: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; MorphoSys: Research Funding; Celtrion: Research Funding; Gilead: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Incyte: Research Funding. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hess:Janssen: Consultancy, Honoraria, Other: personal fees; Celgene: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; Roche: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; Pfizer: Other: personal fees, Research Funding; CTI: Consultancy, Employment, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria. Provencio:Takeda: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Novartis: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; AstraZeneca: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Pierre Fabre: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; Boehringer Ingelheim: Consultancy, Other: Travel, accommodation and expenses, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel, accommodation and expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau; MSD: Consultancy, Other: Travel, accommodation and expenses, Speakers Bureau. Nagy:Novartis: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Robak:Morphosys AG: Research Funding; BeiGene: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding. Maddocks:Teva: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Buske:Amgen: Research Funding; Bayer: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau; Hexal: Honoraria, Speakers Bureau. Ambarkhane:MorphoSys: Employment. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Dirnberger-Hertweck:MorphoSys: Employment. Tillmanns:MorphoSys AG: Employment. Weirather:MorphoSys: Employment.
The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized ...German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.
•The addition of valproic acid to intensive induction therapy in combination with all-trans retinoic acid did not result in an improvement of clinical outcome.•Valproic acid-related hematologic toxicity and higher death rates were observed when valproic acid and idarubicin were given in parallel.
The addition of bevacizumab (BEV) to standard doublet chemotherapy improves outcomes compared with chemotherapy alone in patients with metastatic colorectal cancer (mCRC). The OPAL study examined the ...effect of BEV+FOLFOXIRI followed by 5FU/LV and BEV maintenance on progression-free survival (PFS) in patients with previously untreated unresectable mCRC.
Eligible patients had histologically confirmed mCRC, ECOG performance status ⩽1 and were 18-70 years old. Patients received up to 12 cycles of FOLFOXIRI+BEV q2w (induction phase) followed by up to ⩽40 cycles of 5FU/LV+BEV q2w (maintenance phase). Median PFS was the primary end point; secondary end points included response, OS, secondary resection rate, safety and prognostic value of pharmacogenetic profiling.
Ninety-seven patients were enrolled. Of these, 90 received study medication and formed the safety population: 64 males; median age 58 (range 28-71) years; ECOG performance status 0/1 in 54%/46% patients; and liver only disease in 35 patients. Relative dose intensities were 79-85% for all four drugs. The incidence of adverse events (AEs) was as previously reported and there were no new safety signals. In total, 87 serious AEs occurred in 39 patients (43%). Median PFS was 11.1 months (95% CI 9.4-12.0) and did thus not meet the primary objective of 12 months. Median OS was 32.2 months (95% CI 22.6-36.9). Fifty-two patients were pharmacogenetically profiled.
FOLFOXIRI+BEV was feasible in this molecularly unselected mCRC patient population, showing a high efficacy in terms of survival, overall response and secondary resection rate. Pharmacogenomic profiling revealed no clinically relevant marker.
Tafasitamab is an Fc-modified, humanized anti-CD19 monoclonal antibody, which induces enhanced in vitro antibody-dependent cell-mediated cytotoxicity and phagocytosis. Preclinical studies data ...suggest that tafasitamab+lenalidomide may synergistically enhance cytotoxicity to malignant B-cells. Tafasitamab+lenalidomide is FDA-approved in adult patients with relapsed/refractory DLBCL who are ineligible for autologous stem cell transplantation. R-CHOP is the current standard of care (SOC) for patients with newly-diagnosed DLBCL. Data from the Phase Ib FIRST-MIND (NCT04134936) study in newly-diagnosed DLBCL patients suggest that tafasitamab+lenalidomide when added to R-CHOP is tolerable in patients with treatment-naïve DLBCL.
To assess the efficacy and safety of tafasitamab+lenalidomide+R-CHOP vs R-CHOP alone in previously untreated, high-intermediate and high-risk patients with DLBCL.
FRONT-MIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. Patients will be followed-up for up to 60 months after end of treatment.
Patients will be enrolled from approximately 350 centers in America, Europe, and Asia-Pacific.
Eligible patients (n=880) will be aged 18–80 years with previously untreated local biopsy-proven, CD20-positive DLBCL (IPI ≥3 if >60 years/age-adjusted IPI 2–3 if ≤60 years), and ECOG PS 0–2. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded.
Patients will be randomized to receive six 21-days (D) cycles of tafasitamab (12 mg/kg intravenous IV, D 1, 8, and 15)+lenalidomide (25 mg orally, D1–10)+R-CHOP or six 21-D cycles of tafasitamab placebo (D1, 8, and 15)+lenalidomide placebo (orally, D1–10)+R-CHOP.
The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include investigator-assessed event-free survival, overall survival, and safety.
Not yet available.
As 30–50% of patients overall relapse or are refractory to first-line therapy, there remains a high unmet need to improve treatment options for newly diagnosed patients, particularly those with high-risk DLBCL. The combination of tafasitamab, lenalidomide, and R-CHOP may have synergistic potential. Preliminary data from the FIRST-MIND study suggest that tafasitamab±lenalidomide+R-CHOP is tolerable in patients with treatment-naïve DLBCL. The present study will provide further evaluation of clinical benefits and safety when adding tafasitamab+lenalidomide to current SOC in newly diagnosed patients with high-intermediate and high-risk DLBCL treated with R-CHOP.
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