Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma
ABSTRACT To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).
In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.
In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in >or= 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade >or= 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.
Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.
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ABSTRACT: Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the suitability of positron emission tomography (PET) using the thymidine analogue 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early response assessment upon HCD122 treatment in diffuse large B cell lymphoma (DLBCL). Methods: Immunodeficient mice bearing human DLBCL xenografts (SU-DHL-4) received weekly intraperitoneal injections of HCD122. Tumor growth was followed up until Day 14. Molecular imaging with FLT-PET was performed before (Day 0) and after start of therapy (Day 2 and Day 7). On Day 14 lymphoma xenografts were explanted for immunohistochemical analysis to correlate PET findings with CD40 surface expression on tumor tissue. Results: Treatment with HCD122 significantly delayed tumor growth resulting in a tumor growth inhibition of 45% on Day 14. Significant reduction of tumor-to-background ratio (TBR) of FLT-PET was seen in treated animals on Day 7 and preceded change of tumor volume, thus predicting therapy response to HCD122. Immunohistochemical analysis of xenografts revealed significantly higher CD40 expression on treated than on untreated tissue. Moreover, we found a significant correlation between CD40 expression and FLT-PET response for xenograft tumor treated with HCD122. Conclusions: Treatment of DLBCL with the antagonistic CD40 antibody HCD122 can be monitored with FLT-PET as early as seven days after commencement of therapy and seems to increase CD40 expression on tumor tissue.Advances in Molecular Imaging 04/2015; 5(2). DOI:10.4236/ami.2015.52002.
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ABSTRACT: The recent approvals of two drugs that block the function of the immune checkpoint programmed cell death 1 (PD-1) have firmly planted tumor immunotherapy in the mainstream of clinical oncology. We provide a historical and immunologic context for these recent advances and discuss translational studies that provide insight into the efficacy of cancer immunotherapy at the individual patient level. Copyright © 2015, American Association for the Advancement of Science.Science translational medicine 03/2015; 7(280):280sr1. DOI:10.1126/scitranslmed.3010274 · 14.41 Impact Factor
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ABSTRACT: Immune recognition and elimination of malignant cells require a series of steps orchestrated by the innate and the adaptive arms of the immune system. The majority of tumors have evolved mechanisms that allow for successful evasion of these immune responses. Recognition of these evasive processes led to development of immunotherapeutic antibodies targeting the co-stimulatory and co-inhibitory receptors on T cells, with the goal of enhancement of T cell activation or reversal of tumor-induced T cell inhibition. Several of these agents, such as antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) have already demonstrated significant promise in clinical trials. Clinical benefit of these antibodies as single agents, however, has been limited to a subset of patients and has not been observed in all tumor types. These limitations call for development of rational combination strategies aiming to extend therapeutic benefit to a broader range of patients. These include: 1) modalities that enhance antigen presentation, such as radiation, cryotherapy, chemotherapy, targeted agents, vaccines, toll-like receptor (TLR) agonists, type I interferon, and oncolytic viruses; 2) additional agents aiming to reverse T cell dysfunction, such as other immune checkpoint inhibitors; and 3) agents targeting other immune inhibitory mechanisms, such as inhibitors of indoleamine dioxygenase (IDO), regulatory T cells, and myeloid-derived suppressor cells (MDSC). It is becoming increasingly evident that the efficacy of specific combinations will likely not be universal and that the choice of a treatment modality may need to be tailored to fit the needs of each individual patient.Pharmacology [?] Therapeutics 01/2015; 150. DOI:10.1016/j.pharmthera.2015.01.003 · 7.75 Impact Factor