Arzerra (ofatumumab)

P2, N=135, Active, not recruiting, National Cancer Institute (NCI)

P2, N=53, Active, not recruiting, Northwestern University | Trial completion date: May 2023 --> May 2027

The combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options.

Our data show that S1P signaling can modulate macrophage recruitment and tumor cell killing by anti-CD20 monoclonal antibodies in DLBCL. The administration of S1PR1 inhibitors could enhance the phagocytosis of tumor cells and improve outcomes for patients.

P2, N=37, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed

There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.

P2, N=32, Completed, National Heart, Lung, and Blood Institute (NHLBI) | Active, not recruiting --> Completed

Pts who were MRD+ by both NEST and RQ in the BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 monoclonal antibody ofatumumab (OFA)...A consolidation strategy with more effective agent should be advisable. With these limits, a clinical advantage of the MRD-driven treatment strategy is suggested, although not largely applicable.

The discovery cohort comprised pre-treatment samples from 79 CLL patients enrolled in the NCRI RIAltO trial (NCT01678430) who underwent factorial randomisation to ofatumumab and either bendamustine or chlorambucil, with or without idelalisib. The present study has identified three previously undescribed T-cell subpopulations that appear to influence the risk of infection, SPM, and death in patients with CLL receiving frontline chemo-immunotherapy. Further studies are warranted to validate these findings in the setting of targeted agents and in patients receiving CIT for other haematological malignancies.

Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2)...One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.

Blood samples from 28 patients from GELLC7 trial (NCT03280160, ibrutinib followed by ofatumumab consolidation) were collected before treatment (BT), and 1, 3, 6 and 12 months on treatment (at least two timepoints). Ibrutinib in T cells reduced the expression of exhaustion markers, Tregs and Tfh cells. In CLL cells, we observed a downregulation of markers related to adhesion, immunosuppression and migration, but an overexpression of TMBIM6 in CLL cells that retained migrative capacity towards CXCL12 under ibrutinib. Finally, we identified TMBIM6 expression as an independent poor prognostic factor and a potential novel target for CLL.

Patients were randomly assigned to receive bendamustine or chlorambucil plus ofatumumab, with or without idelalisib. To our knowledge, this is the first study to identify correlations between the re-emergence of non-malignant B-cells following anti-CLL therapy and specific clinical endpoints such as haematopoietic recovery, serum Ig levels, TTP and OS. Although further validation is required in the context of targeted agents, our findings suggest that therapy-induced re-emergence of non-malignancy B-cells may have important biological and clinical implications in CLL.

Patients were randomly assigned to receive ofatumumab plus either bendamustine or chlorambucil, with or without idelalisib. CIT results in profound immune changes that persists up to 18.5 [16.1 – 22.6] months following treatment. Furthermore, the overall effect of these changes further differentiates the CLL-associated immune profile from that of HC, deepening the existing T-cell dysfunction irrespective of chemotherapy choice, or the addition of idelalisib. Our study has important potential implications for patients receiving CIT in a range of clinical settings and supports the move towards more targeted agents that are less likely to cause indiscriminate immune perturbation.

We conjugated a human IgG1 anti-BCMA mAb and an isotype matched nonbinding control mAb (ofatumumab), with the amine-reactive labeling agent B10-NCS to enable 211At radiolabeling... Tumor responses are encouraging with 100% of mice cured of MM after receiving low doses of BCMA targeted 211At. While we have previously demonstrated that 211At-CD38 could eliminate MM in a similar model system, in that setting fewer than 50% of mice bearing the same NCI-H929Luc tumors, and treated with 8 μCi of 211At, survived to day 150 [O'Steen S. Blood, 2019]. In contrast, here we show that 100% of mice are cured after receiving 6 μCi of 211At-BCMA-B10.

This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies.

P2, N=50, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Aug 2023 --> Jan 2024

P2, N=6, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | N=40 --> 6 | Trial completion date: Jun 2023 --> Feb 2023 | Trial primary completion date: Jun 2023 --> Feb 2023

P2, N=44, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

P2, N=45, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Aug 2023 --> Aug 2024

We then discovered that R and ofatumumab differentially synergize with the cytotoxic and cytostatic capabilities of CHOP in separate distinct subsets of B-cell lymphoma cell lines, thereby expanding favorable immunochemotherapy interactions across a greater range of cell lines beyond those induced by R-CHOP. This finding may have immediate clinical significance because both immunochemotherapy combinations are already FDA-approved with no difference in toxicity across phase I, II, and III clinical trials. Therefore, this finding could inform a new precision medicine strategy to provide additional therapeutic benefit to patients with B-cell lymphoma using immunochemotherapy combinations that already meet the clinical standard of care.

Indeed, chemoimmunotherapy regimens used in de novo DLBCL failed to induce a significant complete remission rate (CRR) (R-CHOP, 7%; ofatumumab-CHOP, 27%) [1,2]...Nine (60%) patients received chemo- immunotherapy, 9 (60%) had been exposed to ibrutinib including 4 (26.7%) to both ibrutinib and venetoclax (data collection ongoing for one patient)...Following CAR T-cell infusion with axi-cel (7 patients) or tisa-cel (8 patients), 8 (53.3%) patients were alive, 7 (46.6%) patients died (3 from acute toxicity with two CRS and one neurotoxicity, and 4 from disease progression)...Tocilizumab was administered to 13 (87%) patients... CD19-directed CAR T-cell therapy showed high response rates and an encouraging survival in our series of heavily pretreated RS patients. Frequency of CAR T-cell- specific adverse events was in the range of what is observed in de novo DLBCL while severity appeared higher [3,4].

With a median observation time of 38.6 months (range 1.1–76.3) a total of 981 patients treated first-line (85.4%) or relapsed/refractory (14.6%) with at least one dose of venetoclax plus CD20 antibody (n = 520), venetoclax plus BTKi (n = 297), BTKi (n = 128), or idelalisib (n = 36) were included. All patients received therapy with anti-CD20 antibody obinutuzumab (n = 685), rituximab (n = 231), or ofatumumab (n = 65)... Autoimmune cytopenias may occur with an incidence of 9% in patients with CLL treated with targeted drugs. When comparing different treatment modalities, venetoclax plus BTKi had the highest AIC incidence. Adverse risk factors for AIC were venetoclax-based treatment, advanced Binet stage, female sex and TP53 disruptions.

Using the CD20-targeting antibody ofatumumab, we evaluated chelation of Th for α-particle-emitting and radiotheranostic applications... Commercially available and novel chelators for Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for Zr/Th quantitative imaging and α-particle therapy.

Therapy with anti-CD20 monoclonal antibodies (mAbs), for example, rituximab and ofatumumab, is a well-established treatment for lymphoid malignancies, and CDC is one of the main mechanisms underlying their anti-cancer activity. Previous studies have reported that a gain-of-function in a certain complement component can boost the cytolytic activity of anti-CD20 mAbs. Through reviewing the literature on complement system control and anti-CD20 mAbs, this article aims to provide a thorough understanding of the potential of targeting complement components in lymphoma therapy.

Also, ofatumumab had no statistically significant improvement in the OS of patients with CLL. Thus, ofatumumab-based therapies for CLL patients could be improved by other combinational-based regimens.

Four phase-2 trials of the German CLL Study Group evaluated time-limited combination regimens in treatment-naïve or relapsed/refractory CLL: BAG (venetoclax-obinutuzumab), BCG (idelalisib- obinutuzumab), BIG (ibrutinib-obinutuzumab) and BIO (ibrutinib-ofatumumab), with or without initial debulking with bendamustine. Genetic risk factors such as the IGHV mutation status remain significant prognostic factors for PFS in the context of time-limited treatment with targeted drugs. Acquisition of high-risk markers was rare and resistance mutations were only acquired in 2 of 44 cases. Chronic lymphocytic leukemia, ibrutinib, Prognostic factor, Venetoclax

In the previously treated cohort, prior lines of treatment included chemoimmunotherapy in 73% and ibrutinib + obinutuzumab + venetoclax, bendamustine + ibrutinib + ofatumumab and obinutuzumab + venetoclax in 9% of patients each. The first interim analysis of this international phase II study evaluating treatment with acalabrutinib in very old and/or frail patients with CLL did not show unexpected safety signals in comparison to prior published data. Comorbidities, Chronic lymphocytic leukemia, Clinical trial, Elderly

Within R/R CLL, single-agent ibrutinib was evaluated in 3 randomized phase 3 trials: RESONATE (vs ofatumumab), ALPINE (vs zanubrutinib), and ELEVATE-RR (vs acalabrutinib in patients with del(11q) or del(17p) mutations). In phase 3 randomized trials in R/R CLL, continuous ibrutinib treatment was associated with robust PFS and ORR benefits. Ibrutinib outcomes were consistent between RESONATE and ELEVATE-RR; however, significant differences in the performance of ibrutinib within ALPINE were identified. Indirect comparisons have limitations,since each trial, protocol, and patient profile are unique; however, these results highlight the need for further research on which elements of protocol design, center selection, or treatment delivery may lead to a significant impact on the performance of a given BTKi in clinical trials.

Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2)...In pts with newly diagnosed Ph-negative B-cell ALL receiving hyper-CVAD with sequential blinatumomab, the addition of INO is safe and may improve survival. Acute lymphoblastic leukemia, Clinical trial, Phase II

P2, N=42, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Jul 2023 | Trial primary completion date: Dec 2022 --> Jul 2023

P2, N=37, Active, not recruiting, Roswell Park Cancer Institute | Trial completion date: Feb 2023 --> Dec 2023

P2, N=45, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial primary completion date: Mar 2022 --> Mar 2023

The IAT consisted of antithymocyte globulin Grafalon® (4 x 15 mg/kg), cyclophosphamide (2 x 60 mg/kg) and fludarabine (4 x 40 mg/m²)...Different therapeutic approaches with methylprednisolone pulses, infliximab, adalimumab, ofatumumab, ruxolitinib, pentostatin, sirolimus and extracorporeal photopheresis remained ineffective...Despite the application of methylprednisolone pulses, cyclosporine A, imatinib, ruxolitinib and extracorporeal photopheresis, the cGvHD progressed...Patient 2 has too few T cells for a meaningful Vβ-Spectratyping.CharacteristicsPatient 1Patient 2Age (years)1216SexfemalemaleDiagnosisB precursor ALLcommon ALLDonor of initial HSCTMSD (brother)MUDStem cell sourcebone marrowperipheral bloodConditioningTBI, VP-16TBI, VP-16, ATGGvHD prophylaxiscyclosporine Acyclosporine A, methotrexatecGvHD scoring before IATskin: 3, joints and fascia: 3, lungs: 2, eyes: 1skin: 3, joints and fascia: 3, lungs: 2, eyes: 1CD34+ content of stem cell rescue2.05 x 106/kg2.4 x 106/kgEngraftment after IATleucocytes > 109/l since day 9thrombocytes > 20 x 109/l since day 11leucocytes > 109/l since day 10thrombocytes > 20 x 109/l since day 11Response to IATcomplete responsepartial responsecGvHD scoring after IATskin: 0; joints and fascia: 0; lungs: 2 (residuum of cGvHD); eyes: 0skin: 2; joints and fascia: 2; lungs: 2; eyes: 0Virus reactivationCMVEBVImmunosuppression after IATdiscontinued on day 203low dose methylprednisolone (0.1 mg/kg/d)Last follow-upday 759 after stem cell rescueday 308 after stem cell rescue Two patients with life-threatening SR-cGvHD clearly benefitted from IAT with following re-transplantation of stem cells, while previous long-term immunosuppressive and biological treatment failed. Two patients with life-threatening SR-cGvHD clearly benefitted from IAT with following re-transplantation of stem cells, while previous long-term immunosuppressive and biological treatment failed. Until now, this concept has only been a therapeutic option in some refractory autoimmune diseases. More data is needed to re-evaluate the usage in SR-cGvHD.

P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Jun 2023 | Trial primary completion date: Dec 2022 --> Jun 2023

Rituximab (R) was administered as either 375 mg/m2 weekly; 750 mg/m2 daily on days 1, 2 and 3; or 750 mg/m2 weekly times during cycle one and daily times three for cycle two and three. Obinutuzumab (G) and ofatumumab (O) were administered per FDA standard dosing...Some Pts who achieved a partial response (PR) to initial therapy underwent alemtuzumab (Alem) consolidation, 10mg, administered three times a week for a total of eight weeks. All Pts received anti-microbial prophylaxis consisting of fluconazole, bactrim and acyclovir...Patients without progression at 36 months were found to have higher serum IgA levels. While the Tx landscape for CLL has dramatically changed, the addition of HDMP to an anti-CD20 mAB can be a Tx option for patients desiring short course of Tx, requiring bridging to more definite therapy, or debulking strategy prior to venetoclax based Tx.

Establishing the absence of significant difference in efficacy of frontline targeted therapies in CLL allows the clinician and patient to select therapy based on other factors, namely planned duration, toxicity profile, medication interactions, and cost.Figure 1. 24-month PFS Network and Forest Plot1Chl = Chlorambucil; Acal = Acalabrutinib; Acal/Obin = Acalabrutinib/Obinutuzumab; BR = Bendamustine/Rituximab; Chl/Ofa = Chlorambucil/Ofatumumab; Chl/Ritux = Chlorambucil/Rituximab; Chl/Ritux + Mtn = Chlorambucil/Rituximab + maintenance Rituximab; Flu = Fludarabine; Ibr = Ibrutinib; Ibr/Obin = Ibrutinib/Obinutuzumab; Ibr/Ritux = Ibrutinib/Rituximab; Ibr/Ven = Ibrutinib/Venetoclax; Ven/Obin = Venetoclax/Obinutuzumab; Zan = Zanubrutinib

Our findings were observed prior to the incorporation of CART-19 therapy and other novel agents commonly used in the third line setting such as polatuzumab vedotin, tafasitamab-cxix or loncastuximab tesirine-lpyl.To explore the molecular mechanisms of BCL-xL in r/r DLBCL, we found resistant cell lines have a less expression level of BCL-xL compared to the sensitive cell lines...Silencing of BCL-xL increased the antitumor activity of venetoclax, as well as the complement mediated cytotoxicity of anti-CD20 antibodies (rituximab, obinotuzumab, and ofatumumab) in vitro...Furthermore, in lymphoma xenograft mouse models, silencing of BCL-xL potentiated the anti-tumor activity of rituximab and venetoclax. SCID mice bearing BCL-xL KO Raji cells exhibited a prolonged survival following therapy with rituximab and venetoclax when compared to SCID bearing non-target control Raji cells treated with the same combination (median survival time of 39 days vs 28 days, p<0.05).The data generated here will give us solid preclinical evidence to support the clinical testing of B cell lymphoma specific BCL-xL inhibitor in patients with r/r lymphoma, both as a single agent and in rational combinations.

2010]CPO107 is a bispecific fusion protein based off the anti-CD20 ofatumumab antibody with one Fab fragment being replaced with a SIRPα domain, which natively binds CD47...The monoclonal antibody Magrolimab (Hu5F9-G4) in combination with rituximab induced a high rate of tolerable and durable complete responses in heavily pretreated patients (pts) with rituximab-refractory DLBCL and FL [Chao et al...Upon reaching the MTD or RP2D, Part B of the study will enroll approximately 15 pts with CD20+ NHL to explore preliminary efficacy. The study has been registered on ClinicalTrials.gov (NCT04853329).

P2, N=32, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial completion date: Sep 2022 --> Sep 2023

Thirty (68%) pts went on to receive further treatment (19 pts on BTK based regimens, 2 pts received venetoclax monotherapy, 5 pts received combined venetoclax and ibrutinib, 3 pts received chemoimmunotherapy, and 1 pt received obinutuzumab monotherapy). The PFS was similar to that of similarly designed trials with rituximab monotherapy and rituximab in combination with alemtuzumab, respectively. Further internal matched analysis is being conducted to compare time to second treatment.