A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma

Cornell University, Итак, New York, United States
Annals of Oncology (Impact Factor: 7.04). 08/2007; 18(7):1216-23. DOI: 10.1093/annonc/mdm114
Source: PubMed


Galiximab is a monoclonal antibody that targets CD80, a costimulatory molecule constitutively expressed on follicular and other lymphomas. Modest single-agent clinical activity and tolerability were demonstrated in a phase I study in relapsed or refractory, follicular non-Hodgkin's lymphoma (NHL). A phase I/II study was conducted to evaluate galiximab in combination with a standard course of rituximab. Safety, pharmacokinetics, and efficacy were evaluated.
Patients with follicular NHL who had relapsed or failed primary therapy were enrolled. Rituximab-refractory patients (no response or a response with time to progression <6 months) were excluded. Patients received 4 weekly i.v. infusions of galiximab (125, 250, 375, or 500 mg/m(2)) and rituximab (375 mg/m(2)). International Workshop Response Criteria (IWRC) were used to evaluate response.
Seventy-three patients received treatment. All had received at least one prior lymphoma therapy; 40% were rituximab naive. Infusions were delivered in an outpatient setting and were well tolerated. The most common study-related adverse events (AE) were lymphopenia, leukopenia, neutropenia, fatigue, and chills. The overall response rate at the recommended phase II dose of galiximab (500 mg/m(2)) was 66%: 19% complete response, 14% unconfirmed complete response, and 33% partial response. The median progression free survival was 12.1 months. Combination therapy did not appear to alter pharmacokinetics.
These results indicate that galiximab can be safely combined with a standard course of rituximab. This doublet biologic approach offers the potential to avoid or delay chemotherapy or to integrate with other lymphoma therapies. A phase III, randomized study evaluating clinical benefit of rituximab versus the combination has been initiated.

Download full-text


Available from: Arturo Molina, Sep 24, 2015
19 Reads
  • Source
    • "This concept is supported by reports of at least two human-macaque chimeric mAbs, galiximab (IDEC-114, anti-CD80) and lumiliximab (IDEC-152, anti-CD23), in which the VH and VL from cynomolgous macaques were fused with human constant regions. In phase I and II clinical studies, no human anti-galiximab or anti-lumiliximab antibodies were detected in humans [34,35]. Finally, if needed, it would be easier to change a small number of amino acids in the framework region of the macaque VH and VL regions to produce complete germline humanization [36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The outbreaks of emerging infectious diseases caused by pathogens such as SARS coronavirus, H5N1, H1N1, and recently H7N9 influenza viruses, have been associated with significant mortality and morbidity in humans. Neutralizing antibodies from individuals who have recovered from an infection confer therapeutic protection to others infected with the same pathogen. However, survivors may not always be available for providing plasma or for the cloning of monoclonal antibodies (mAbs). The genome and the immunoglobulin genes in rhesus macaques and humans are highly homologous; therefore, we investigated whether neutralizing mAbs that are highly homologous to those of humans (human-like) could be generated. Using the H5N1 influenza virus as a model, we first immunized rhesus macaques with recombinant adenoviruses carrying a synthetic gene encoding hemagglutinin (HA). Following screening an antibody phage display library derived from the B cells of immunized monkeys, we cloned selected macaque immunoglobulin heavy chain and light chain variable regions into the human IgG constant region, which generated human-macaque chimeric mAbs exhibiting over 97% homology to human antibodies. Selected mAbs demonstrated potent neutralizing activities against three clades (0, 1, 2) of the H5N1 influenza viruses. The in vivo protection experiments demonstrated that the mAbs effectively protected the mice even when administered up to 3 days after infection with H5N1 influenza virus. In particular, mAb 4E6 demonstrated sub-picomolar binding affinity to HA and superior in vivo protection efficacy without the loss of body weight and obvious lung damage. The analysis of the 4E6 escape mutants demonstrated that the 4E6 antibody bound to a conserved epitope region containing two amino acids on the globular head of HA. Our study demonstrated the generation of neutralizing mAbs for potential application in humans in urgent preparedness against outbreaks of new influenza infections or other virulent infectious diseases.
    PLoS ONE 06/2013; 8(6):e66276. DOI:10.1371/journal.pone.0066276 · 3.23 Impact Factor
  • Source
    • "Galiximab is a chimeric human–primate anti- CD80 mAb with single-agent activity and excellent tolerability in previous treated FL [Czuczman et al. 2005]. A phase I/II study evaluating the combination of galiximab and rituximab in patients with relapsed/refractory FL showed an ORR of 66% and a median PFS of 12.1 months [Leonard et al. 2007]. In 61 untreated FL patients, this regimen appeared efficacious ( "
    [Show abstract] [Hide abstract]
    ABSTRACT: Indolent non-Hodgkin's lymphomas (iNHLs) include follicular lymphomas (FL), marginal-zone lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and small lymphocytic lymphoma. First-line standard therapy in advanced, symptomatic iNHL consists of rituximab-based immunochemotherapy. The recent rediscovery of the 'old' chemotherapeutic agent bendamustine, an alkylating agent with a peculiar mechanism of action, has added a new effective and well-tolerated option to the therapeutic armamentarium in iNHL, increasing response rates and duration. However, patients invariably relapse and subsequent active and well-tolerated agents are needed. In recent years a large number of new targeted agents have been tested in preclinical and clinical experimentation in FL and indolent nonfollicular lymphoma (iNFL), including the new monoclonal antibodies binding CD20 or other surface antigens, immunoconjugates and bispecific antibodies. Moreover novel agents directed against intracellular processes such as proteasome inhibitors, mTOR inhibitors and agents that target the tumour microenvironment, notably the immunomodulatory agent lenalidomide, are under active clinical investigation. The development of these new drugs may change in the near future the approach to iNHL patients, leading to better tolerated and effective therapy regimens.
    04/2013; 4(2):133-48. DOI:10.1177/2040620712466865
  • Source
    • "To enhance efficacy and improve patient outcome, therapeutic mAbs are typically used in combination with one or more chemotherapeutic in the clinic (Keating, 2010). Recently, the combination of rituximab with mAbs directed against other B cell antigens has gained significant interest and is being explored in clinical trials (Stein et al, 2004; Strauss et al, 2006; Leonard et al, 2007, 2008). Preclinical studies in SCID mouse lymphoma models have shown that the combination of CD20- targeted mAbs with the CD22 mAb epratuzumab or a CD19- targeted immunotoxin (BU-12-saporin) has better tumour growth inhibition than the single agents (Stein et al, 2004; Flavell et al, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human cluster of differentiation (CD) antigen 19 is a B cell-specific surface antigen and an attractive target for therapeutic monoclonal antibody (mAb) approaches to treat malignancies of B cell origin. MEDI-551 is an affinity-optimized and afucosylated CD19 mAb with enhanced antibody-dependent cellular cytotoxicity (ADCC). The results from in vitro ADCC assays with Natural Killer cells as effector cells, demonstrate that MEDI-551 is effective at lower mAb doses than rituximab with multiple cell lines as well as primary chronic lymphocytic leukaemia and acute lymphoblastic leukaemia samples. Targeting CD19 with MEDI-551 was also effective in several severe combined immunodeficiency lymphoma models. Furthermore, the combination of MEDI-551 with rituximab resulted in prolonged suppression of tumour growth, demonstrating that therapeutic mAbs with overlapping effector function can be combined for greater tumour growth inhibition. Together, the data demonstrate that MEDI-551 has potent antitumour activity in preclinical models of B cell malignancies. The results also suggest that the combination of the ADCC-enhanced CD19 mAb with an anti-CD20 mAb could be a novel approach for the treatment of B cell lymphomas.
    British Journal of Haematology 09/2011; 155(4):426-37. DOI:10.1111/j.1365-2141.2011.08857.x · 4.71 Impact Factor
Show more